Compounds that modulates ampa receptor function

ABSTRACT

The invention provides compounds of the formula (I): (I) wherein A 1 , A 2 , R 2 , R 4 , B 1 , B 2 , X, X 1 , n, a and b are as defined are defined in the specification, to pharmaceutical compositions comprising the compounds and the compounds for use as medicaments. The compounds potentiate AMPA receptor function and are expected to be useful in the treatment of central nervous system disorders, for example in the treatment of depressive disorders, mood disorders and cognitive dysfunction associated with neuropsychiatric disorders such as schizophrenia.

This invention relates to compounds of the formula (I) defined herein;to pharmaceutical compositions comprising the compounds. Morespecifically, the invention relates to compounds which are useful asAMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamatereceptor modulators. The invention also relates to uses of the compoundsand methods of treatment employing the compounds, particularly in thetreatment or prevention of diseases or conditions in which potentiationof the AMPA receptor is beneficial, for example in the treatment ofneurological or neuropsychiatric disease, particularly the treatment ofdepressive disorders, mood disorders and cognitive dysfunctionassociated with neuropsychiatric disorders such as schizophrenia. Theinvention further comprises methods for preparing the compounds andintermediates used in the preparation of the compounds.

BACKGROUND

Glutamate is the major mediator of excitatory neurotransmitter in themammalian brain, and is involved in rapid point-to-point (synaptic)communication between neurons. The functions of glutamate are mediatedvia three types of fast acting ion channels; the kainate, AMPA andN-methyl-D-aspartate (NMDA) subtypes; and by the more modulatorymetabotropic G-protein coupled (mGlu1-8) receptors.

AMPA receptors are tetrameric comprising four subunits (GluA1-GluA4)(Traynelis et al., Glutamate receptor ion channels: structure,regulation, and function; Pharmacol. Rev. 2010, 62, 405-496). FunctionalAMPA receptors can be formed from homo- or hetero-tetramers. Nativereceptors are almost exclusively heteromeric which leads to a diversityof receptor subunit composition in the human brain.

Studies of the X-ray structure of the membrane-bound channel show thatthe AMPA receptor comprises (1) an amino terminal domain (ATD), which isinvolved in the assembly of subunits and is the site of action for anumber of molecules that modulate AMPA receptor function; (2) a ligandbinding domain (LBD) including two polypeptide segments S1 and S2, whichbinds glutamate; (3) a transmembrane domain (TMD) containing apore-forming ion channel; and (4) a C-terminal intracellular domain. Inaddition to the various subunit permutations, an additional layer ofcomplexity is created by the existence of a number of splice variants(flip and flop variants) and sites for post-translational modification(Seeburg et al.; RNA editing of brain glutamate receptor channels:mechanism and physiology. Brain Res Brain Res Rev. 1998, 26: 217-229).RNA editing results in a positively charged arginine (R) residuereplacing the genomically encoded glutamine (Q) in the M2 re-entrantloop of the GluA2 subunit, thereby restricting Ca²⁺ flux through thechannel and essentially rendering the receptor permeable to just Na⁺ andK⁺, which is deemed crucial for adult synaptic function and plasticity(Sommer et al.; RNA editing in brain controls a determinant of ion flowin glutamate-gated channels; Cell 1991, 105: 11-19; and Seeburg et al.;Genetic manipulation of key determinants of ion flow in glutamatereceptor channels in the mouse. Brain Res. 2001, 907, 233-243).Extensive structural studies have been carried out on LBD constructs(Sobolevsky et al., Nature, 2009, 462, 745-756).

AMPA receptors are the most highly-expressed ionotropic glutamatereceptors in the brain and are responsible for the majority of fastsynaptic transmission. AMPA receptor mediated cell depolarization leadsto calcium influx via NMDA receptors and the induction of synapticplasticity (Derkach et al., 2007, Nat. Rev. Neurosci., 8:101-113).

Synaptic plasticity is the cellular process that underlies learning andmemory. AMPA receptors are actively trafficked into synapses in responseto neuronal activation and a functional correlate of this is that theyplay a crucial role in long-term potentiation, the electrophysiologicalcorrelate of synaptic plasticity (Malinow et al., Annual Review ofNeuroscience, 2002, 25, 103-126).

Abnormalities in glutamatergic neurotransmissions are associated with avariety of CNS disorders and the alterations in the function of thekainate, AMPA and/or NMDA subtypes of glutamate ion channels have beenexplored as therapeutic targets. Of these ion channel subtypes, AMPAreceptors interact very closely with NMDA receptors and together theyare associated with synaptic plasticity.

AMPA modulators can also produce effects on in vivo electrophysiologicalmeasurements such as long-term potentiation, AMPA induced currents andneuronal firing rates (Hampson et al., Psychopharmacology (Berl). 2009,202(1-3), 355-69). The observation that AMPA receptor expressionincreases after learning a behavioural task (Cammarota et al.,Neurobiol. Learn. Mem., 1995, 64, 257-264) or after exposure to a singlefear-inducing stimulus (Liu et al., Nature neuroscience, 2010, 13(2),223-31) further emphasizes the importance of AMPA receptors in relationto learning, memory and synaptic plasticity.

In view of the critical role of AMPA receptors in the synapticplasticity that underlies cognition, AMPA receptor modulators areexpected to useful in enhancing cognitive function. AMPA receptormodulators may also be useful in the treatment of cognitive dysfunctionassociated with medical disorders (e.g. cognitive dysfunction associatedwith psychotic disorders, depressive disorders or neurodegenerativedisorders). AMPA receptor modulators may be useful in the treatment of,for example, schizophrenia, Alzheimer's disease, bipolar disorder,attention deficit hyperactivity disorder, depression or anxiety,particularly in the treatment of cognitive dysfunction associated withthese disorders.

Although potentiation of AMPA receptors has been shown to promotecognition, it has also been found that AMPA potentiation by certaincompounds is linked to undesirable convulsant effects and seizures(Yamada Exp. Opin. Investig. Drugs, 2000, 9, 765-777). Direct activationof AMPA receptors using receptor agonists increases the risk ofoverstimulation and the induction of convulsant effects. This has led toresearch into the development of allosteric (i.e., non-glutamate bindingsite) AMPA receptor potentiators as a means of enhancing neuroplasticityand thus treating various neuropsychiatric disorders (Kalivas et al.,Neuropsychopharmacology, 2008; 33:2).

Positive allosteric modulators (PAMs) of the AMPA receptor (AMPA-PAMs)stabilize the AMPA receptor in its active conformation followingglutamate binding resulting in increased synaptic currents, therebypromoting synaptic transmission and plasticity (Mellor. The AMPAreceptor as a therapeutic target: current perspectives and emergingpossibilities. Future Med. Chem. 2010, 2, 877-891; and O'Neill et al.,AMPA receptor potentiators as cognitive enhancers. Idrugs, 2007, 10,185-192). Positive allosteric modulators (PAMs) are use-dependent drugsand as such only act when endogenous glutamate is released. PAMpotentiation of AMPA receptors may therefore reduce the risk ofundesirable side effects associated with AMPA potentiation such asconvulsions.

AMPA receptor potentiation using PAMs have shown beneficial effects,including increased ligand affinity for the receptor (Arai et al.,Neuroreport. 1996, 7, 221, 1-5.); reduced receptor desensitization andreduced receptor deactivation (Arai et al., 2000, 58, 802-813); andfacilitate the induction of LTP in vivo (Staubli et al., Proc. Natl.Acad. Sci. 1994, 91(1), 1158-1162). The efficacy of various AMPAreceptor PAMs in pre-clinical and clinical models of psychiatricdisorders, such as schizophrenia, are described in (Morrow et al.,Current Opinion in Drug Discovery and Development, 2006, 9(5), 571-579).

Around 1% of the population will suffer from schizophrenia at some pointin their life. Symptoms such as paranoia and/or hearing voices can bereasonably well treated by existing medications. However, known drugshave little effect on other symptoms of the disease including lack ofmotivation, impaired social function, and, particularly, impairedcognition. Cognitive dysfunction manifests itself as difficulties withattention, memory and problem solving and result in patientsexperiencing a “brain fog”. These largely untreated symptoms remain ahuge barrier to the resumption of a fully functional, “normal” life foraffected individuals.

The recognition of the unmet clinical need in schizophrenia triggeredthe NIH- and FDA sponsored Measurement and Treatment Research to ImproveCognition in Schizophrenia (MATRICS) initiative that mapped out theregulatory path for treatments for the cognitive impairment associatedwith schizophrenia (CIAS). Most therapeutic approaches to the treatmentof cognitive impairment in schizophrenia have focused on the glutamatesystem aiming to either directly or indirectly increase NMDA receptorfunction (Field et al., Trends Mol. Med., 2011, 17, 689-98). Directapproaches to increasing NMDA receptor function include glycinetransporter type 1 (GlyT1) inhibitors (e.g. R1678, Roche). Indirectapproaches include mGluR2 positive allosteric modulators (PAMs), mGluR5PAMs, mGluR2/3 agonists (for example pomaglumetad methionil, LY2140023Lilly) and D-amino acid oxidase inhibitors. However, there remains aneed for new therapies which improve cognitive performance in subjectswith schizophrenia and other CNS conditions.

Clinical studies have shown that ketamine provides rapid relief from thesymptoms of depression, often in a matter of minutes. This finding hasgenerated significant research interest, because conventionalanti-depressants such as SSRI's often take weeks or even months to showanti-depressant effects. Initial studies also suggest that ketamine mayhave the potential to provide potent fast-acting antidepressant effectseven in traditionally difficult to treat patients with severe treatmentresistant depression (Berman et al.; Antidepressant effects of ketaminein depressed patients; Biol. Psychiatry. 2000, 47(4), 351-354). Morerecently Daly et al., JAMA Psychiatry, 2018, 75(2), 139-148) report aphase 2 study showing that intranasal administration esketamine wasefficacious in patients with treatment-resistant depression and that theonset of effects were rapid and sustained. However, ketamine has severalside-effects, including hallucinogenic and addictive properties, whichwould make abuse of the drug likely. It is therefore unlikely thatketamine will be widely adopted as a treatment for depression.

It has recently been found that the antidepressant effects observed withketamine are attributable to a metabolite of ketamine,(2R,6R)-hydroxynorketamine, and that this metabolite acts as an AMPAreceptor potentiator. In mouse models, the metabolite provides rapidanti-depressant-like effects which persist for at least three days(Zanos et al., NMDA receptor inhibition-independent antidepressantactions of a ketamine metabolite. Nature, May 4, 2016) Aleksandrova etal., (J. Psychiatry. Neurosci., 2017; 42(4), 222-229) also indicatesthat AMPA receptors play a key role in mediating the anti-depressanteffects of ketamine and suggests that agents which enhance the functionof AMPA receptors may be beneficial in the treatment of depression.

Accordingly, AMPA receptor potentiators may be useful in the treatmentof, for example, depressive disorder (e.g. major depressive disorder,persistent depressive disorder (dysthymia) or substance/medicationinduced depressive disorders), anxiety or bipolar-disorders. AMPAreceptor potentiators may be particularly useful in the treatment oftreatment resistant depressive disorders, for example in the treatmentof depression that is resistant to conventional anti-depressanttherapies including, but not limited to, tricyclic antidepressants,MAOIs and/or SSRIs.

S47445 is a tricyclic AMPA-PAM of the formula:

This compound is described to be a selective AMPA-PAM and showspro-cognitive effects in rodent models as well as providingneuroprotective effects. The compound is stated to be in clinical trialsfor the treatment of major depressive disorder and Alzheimer's disease(Bretin et al.; Pharmacological characterisation of S 47445, a novelpositive allosteric modulator of AMPA receptors; PLoS ONE. 2017, 12(9),e0184429).

Goffin et al., describe certain 7-phenoxy-substituted3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides as AMPA-PAMs (J. Med.Chem., 2018, 61 (1), pp 251-264).

WO2009/147167 discloses certain indane derivatives which are describedas potentiators of AMPA receptors.

WO2007/107539, WO2008/053031, WO2008/148832, WO2008/148836 and Ward etal., J. Med. Chem. 2011, 54, 78-94 disclose certain pyrazole derivativesas potentiators of AMPA receptors.

WO2010/150192 describes certain isopropylsulphonamide derivatives aspotentiators of AMPA receptors. This patent application discloses thecompound PF-4958242 as example 4. It has been reported that PF-4958242provided a relatively narrow therapeutic window between thepro-cognitive effects and pro-convulsant activity (J. Med. Chem., 2015,58 (10), 4291-4308).

WO2009062930; WO2009053448; WO2009038752; WO2007107539; Ward et al.,British Journal of Pharmacology, 2010, 160, 181-190, 2010; and Ward etal., British Journal of Pharmacology, 2017, 174, 370-385, describecertain compounds that are stated to be AMPA receptor potentiators.

There remains a need for compounds which potentiate AMPA receptors to,for example, provide a pro-cognitive effect. There is also a need forpotentiators of AMPA receptors which have a wide therapeutic windowbetween the desirable pro-cognitive effects and the onset of undesirableside-effects, particularly pro-convulsant activity.

An object of the present invention is to provide compounds whichpotentiate AMPA receptors. Such compounds may be useful for thetreatment of diseases associated with glutamatergic disorders, forexample as described herein, including but not limited to the use of thecompounds in the treatment of major depressive disorder, bipolardisorders or Alzheimer's disease. The compounds may be useful forenhancing cognitive function and/or synaptic plasticity and/or animbalance in excitatory/inhibitory neurotransmission, particularly whenassociated with central nervous system (CNS) disorders. In particularthe compounds may be useful in the treatment of neurological orneuropsychiatric disease. More particularly the compounds may be usefulfor the treatment of cognitive impairment associated with a neurologicalor neuropsychiatric disease.

BRIEF SUMMARY OF THE DISCLOSURE

In accordance with one aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable saltthereof:

A¹ is N or CR¹;A² is N or CR³;and wherein only a single one of A¹ and A² may be N;R¹ is selected from the group consisting of: H, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A1) and —C(O)NR^(A1)R^(B1);R² is selected from the group consisting of: H, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A2) and —C(O)NR^(A2)R^(B2);R³ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,—C₁₋₄ alkyl-OR^(A3) and —C(O)NR^(A3)R^(B3);each X is independently H or F, provided at least one X is F;B¹ and B² are independently CH or N;R⁴ is halo;X¹ is O or CH₂;R^(A1), R^(B1), R^(A2), R^(B2), R^(A3) and R^(B3) are each independentlyselected from: H and C₁₋₄ alkyl;a is an integer selected from 0, 1 or 2;b is an integer selected from 0, 1 or 2;a+b is 0, 1, 2 or 3; andn is 0, 1 or 2;with the following provisos:(i) R¹, R² and R³ are not all H;(ii) when A¹ is N, at least one of R² and R³ is C₁₋₄ alkyl or C₁₋₄haloalkyl;(iii) when A² is N, at least one of R¹ and R² is C₁₋₄ alkyl or C₁₋₄haloalkyl; and(iv) when A¹ is CR¹, R¹ is —CH₂OH and B¹ is N, then R² is not H.

In accordance with another aspect of the present inventions there isprovided a compound of the formula (I), or a pharmaceutically acceptablesalt thereof:

A¹ is N or CR¹;A² is N or CR³;and wherein only a single one of A¹ and A² may be N;R¹ is selected from the group consisting of: H, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A1) and —C(O)NR^(A1)R^(B1);R² is selected from the group consisting of: H, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A2) and —C(O)NR^(A2)R^(B2);R³ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,—C₁₋₄ alkyl-OH and —C(O)NR^(A3)R^(B3);each X is independently H or F, provided at least one X is F;B¹ and B² are independently CH or N;R⁴ is halo;X¹ is O or CH₂;R^(A1), R^(B1), R^(A2), R^(B2), R^(A3) and R^(B3) are each independentlyselected from: H and C₁₋₄ alkyl;a is an integer selected from 0, 1 or 2;b is an integer selected from 0, 1 or 2;a+b is 0, 1, 2 or 3; andn is 0, 1 or 2;with the following provisos:(i) R¹, R² and R³ are not all H;(ii) when A¹ is N, at least one of R² and R³ is C₁₋₄ alkyl or C₁₋₄haloalkyl;(iii) when A² is N, at least one of R¹ and R² is C₁₋₄ alkyl or C₁₋₄haloalkyl;(iv) when A¹ is CR¹, R¹ is —CH₂OH and B¹ is N, then R² is not H; and(v) when A¹ is CR¹, R¹ is —CN and B² is N, then R² is not H.

Also provided is a pharmaceutical formulation comprising a compound ofthe invention and a pharmaceutically acceptable excipient.

In some embodiments the pharmaceutical composition may be a combinationproduct comprising an additional therapeutic agent. The additionaltherapeutic agent may be one or more agents used in the treatment of aCNS condition, for example a neurological or psychiatric condition,particularly therapeutic agents used for the treatment of psychoticconditions such as schizophrenia and related conditions. The additionaltherapeutic may be one or more agents used in the treatment ofdepressive disorders (e.g. major depressive disorders). Additionaltherapeutic agents that may be used together with the compounds of theinvention are set out in the Detailed Description of the inventionbelow.

Also provided is a compound of the invention for use as a medicament.

Also provided a compound of the invention for use in the treatment ofglutamatergic disorders, especially glutamatergic disorders modulated byan AMPA receptor.

Also provided is a compound of the invention for use in the treatment ofa condition which is modulated by an AMPA receptor. Suitably thecompound of the invention is for use in the treatment of a condition inwhich AMPA receptor function is impaired.

Also provided are methods of treating a condition which is modulated byan AMPA receptor in a subject in need thereof by administering aneffective amount of a compound of the invention to the subject.

A compound of the invention may be for use in the treatment of acondition in which potentiation of an AMPA receptor is beneficial.Accordingly, it may be that the compound of the invention is for use inenhancing synaptic plasticity in a subject. It may be that the compoundof the invention is for use in the treatment of an imbalance inexcitatory/inhibitory neurotransmission in a subject.

It may be that the compound of the invention is for use in the treatmentor prevention of central nervous system (CNS) disorders associated withan alteration in one or more of cognitive function, synaptic plasticity,or an imbalance in excitatory/inhibitory neurotransmission. For example,a compound of the invention may be for use in the treatment of any ofthe central nervous system (CNS) disorders disclosed herein, includingneurological or neuropsychiatric disorders, for example a conditionselected from schizophrenia, bipolar disorder, attention-deficithyperactivity disorder (ADHD), depression, Alzheimer's disease,Huntington's disease, Parkinson's disease, Down syndrome and otherneurodevelopmental disorders, motor neuron diseases (e.g. amyotrophiclateral sclerosis), ataxia, respiratory depression and hearing disorders(for example hearing loss and tinnitus). It may be that the compound ofthe invention is for use in the treatment of obsessive-compulsivedisorder, addiction or mood disorders (including major depressivedisorders and bipolar disorders). In some embodiments, a compound of theinvention is for use in the treatment of a depressive disorder, forexample the treatment of a depressive disorder that is resistant toconventional anti-depressant therapies. In some embodiments, a compoundof the invention is for use in the treatment of a depressive disorder ora mood disorder (e.g., a major depressive disorder, an anxiety disorder,a disruptive mood dysregulation disorder, anhedonia or suicidal ideation(suicidal thoughts)).

Also provided is a compound of the invention for use in the alterationof cognitive function, particularly for the enhancement of cognitivefunction, in a subject. More particularly there is provided a compoundof the invention for use in the treatment of a cognitive impairment.Still more particularly there is provided a compound of the inventionfor use in the treatment of cognitive impairment associated with adisease or a condition. It may be that a compound of the invention isfor use in the treatment of cognitive impairment associated with apsychiatric or neurological disorder, for example any of the psychiatricor neurological disorders described herein.

In a particular embodiment, there is provided a compound of theinvention is for use in the treatment of cognitive dysfunctionassociated with schizophrenia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results from the sub-chronic PCP-induced reversallearning in female Lister Hooded rats study described in the Examples inwhich one of the exemplified compounds, UoS26478 was tested compared torisperidone. The FIGURE shows the mean % of correct lever presses in theinitial phase and the reversal phase of the study (n=9-10 per group).“veh” refers to saline vehicle, “scPCP” refers to sub-chronicphencyclidine. “+3.0”, “+10” and “+30” refers to the dose (mg/kg) ofUoS26478 orally administered to the rats. “Risp” refers to risperidoneand this was administered I.P. at a dose of 0.1 mg/kg).

DETAILED DESCRIPTION

Given below are definitions of terms used in this application. Any termnot defined herein takes the normal meaning as the skilled person wouldunderstand the term.

Reference herein to a “compound of the invention” is a reference to anyof the compounds disclosed herein including compounds of the formulae(I), (II), (III), (IV), (V), (VI) and (VII) or a pharmaceuticallyacceptable salt, solvate, or salt of a solvate thereof, including any ofthe Examples listed herein.

The term C_(m-n) refers to a group with m to n carbon atoms.

The term “halo” refers to one of the halogens, group 17 of the periodictable. In particular the term refers to fluorine, chlorine, bromine andiodine. Preferably, the term refers to fluorine or chlorine.

The term “C₁₋₄ alkyl” refers to a linear or branched hydrocarbon chaincontaining 1, 2, 3 or 4 carbon atoms, for example methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl and tert-butyl.

The term “C₁₋₄ haloalkyl”, refers to a C₁₋₄ alkyl group substituted withat least one halogen atom independently chosen at each occurrence, forexample fluorine, chlorine, bromine and iodine. The halogen atom may bepresent at any position on the C₁₋₄ alkyl chain. For example, C₁₋₄haloalkyl may refer to chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chloroethyl (e.g. 1-chloroethyl or 2-chloroethyl),trichloroethyl (e.g. 1,2,2-trichloroethyl, 2,2,2-trichloroethyl),fluoroethyl (e.g. 1-fluoroethyl or 2-fluoroethyl), trifluoroethyl (e.g.1,2,2-trifluoroethyl or 2,2,2-trifluoroethyl), chloropropyl,trichloropropyl, fluoropropyl, trifluoropropyl. A C₁₋₄ haloalkyl groupmay be a C₁₋₄ fluoroalkyl group, i.e. a C₁₋₄ alkyl group substitutedwith at least one fluorine atom (e.g. fluoromethyl, difluoromethyl ortrifluoromethyl, particularly trifluoromethyl).

The term “—C₁₋₄alkyl-OR^(Ax)”, where x=1, 2 or 3, refers to a C₁₋₄ alkylgroup substituted by an —OR^(Ax) group. Examples of —C₁₋₄alkyl-OR^(Ax)groups include —CH₂OH, —CH₂OMe, —CH₂OEt, —CH₂CH₂OH, —CH₂CH₂OMe,—CH(OH)CH₃, —CH(OMe)CH₃, —CH₂CH(OH)CH₃ or —CH₂CH(OMe)CH₃.

The term “C₃₋₄ cycloalkyl” includes a saturated hydrocarbon ring systemcontaining 3 or 4 carbon atoms (cyclopropyl or cyclobutyl).

The group R⁴ (when present) may be located on any carbon atom in thecentral ring of formula (I). For example, when B¹ and/or B² are CH, anR⁴ group may be present on the carbon represented by B¹ and/or B².

In the compounds of the invention only a single one of A¹ and A² may beN. Thus A¹ may be CR¹ and A² may be CR³; or A¹ may be N and A² is CR³;or A¹ may be CR¹ and A² is N. However, A¹ and A² are not both Ntogether.

A bond terminating in a “

” or “*” represents that the bond is connected to another atom that isnot shown in the structure. A bond terminating inside a cyclic structureand not terminating at an atom of the ring structure represents that thebond may be connected to any of the atoms in the ring structure whereallowed by valency.

The invention contemplates pharmaceutically acceptable salts of thecompounds of the invention in so far as such compounds may form salts.These may include the acid addition and base salts of the compounds.These may be acid addition and base salts of the compounds. Suitablepharmaceutically acceptable salts are described in for example “Handbookof Pharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002). Salts may be formed usingwell known methods.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J. Pharm. Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of the invention includereferences to salts, solvates and complexes thereof and to solvates andcomplexes or salts thereof.

Compounds of the invention may exist in a single crystal form or in amixture of crystal forms or they may be amorphous all such forms areencompassed by the present invention. Thus, compounds of the inventionintended for pharmaceutical use may be administered as crystalline oramorphous products. They may be obtained, for example, as solid plugs,powders, or films by methods such as precipitation, crystallization,freeze drying, or spray drying, or evaporative drying. Microwave orradio frequency drying may be used for this purpose.

Certain compounds of the invention are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all optical isomers of the compounds of theinvention. Where a compound has a stereocentre, both (R) and (S)stereoisomers are contemplated by the invention, equally mixtures ofstereoisomers or a racemic mixture are contemplated by the presentapplication. Where the compound is a single stereoisomer the compoundsmay still contain other enantiomers as impurities. Hence a singlestereoisomer does not necessarily have an enantiomeric excess (e.e.) of100% but could have an e.e. or d.e. of about at least 85%.Enantiomerically pure forms are a particular aspect of the invention.Conventional techniques for the preparation/isolation of individualenantiomers when necessary include chiral synthesis from a suitableoptically pure precursor or resolution of the racemate (or the racemateof a salt or derivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically H PLC, on an asymmetric resin with a mobile phase consistingof a hydrocarbon, typically heptane or hexane, containing from 0 to 50%by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% byvolume of an alkylamine, typically 0.1% diethylamine. Concentration ofthe eluate affords the enriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel and S. H. Wilen (Wiley, 1994).

The present invention also includes all pharmaceutically acceptableisotopically-labelled compounds of formulae (I) to (VII) defined herein,wherein one or more atoms are replaced by atoms having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number most commonly found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, (D) mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labelled compounds can generally be prepared byconventional techniques known to those skilled in the art or byprocesses analogous to those described using an appropriateisotopically-labelled reagent in place of the non-labelled reagentpreviously employed.

Compounds of the invention may exist in a number of different tautomericforms and references to compounds of the invention include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by compounds of theinvention.

Prodrugs of the compounds of the invention are also contemplated withinthe scope of the invention. A prodrug is a compound which acts as a drugprecursor which, upon administration to a subject, undergoes conversionby metabolic or other chemical processes to yield a compound of formulae(I) to (VII) defined herein. For example, an —OH group may be convertedto an ester or a carbamate, which upon administration to a subject willundergo conversion back to the free hydroxyl group. Examples of prodrugsand their uses are well known (e.g., Berge et al., “PharmaceuticalSalts”, J. Pharm. Sci. 1977, 66, 1-19). The prodrugs can be prepared insitu during the final isolation and purification of the compounds, or byseparately reacting the purified compound with a suitable esterifyingagent.

The terms “treating”, or “treatment” refer to any beneficial effect inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The term“treating” and conjugations thereof, include prevention of an injury,pathology, condition, or disease.

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, or reduce oneor more symptoms of a disease or condition). An example of an “effectiveamount” is an amount sufficient to contribute to the treatment,prevention, or reduction of a symptom or symptoms of a disease, whichcould also be referred to as a “therapeutically effective amount.” A“reduction” of a symptom or symptoms means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. Theexact amounts will depend on the purpose of the treatment, and will beascertainable by one skilled in the art using known techniques (see,e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd,The Art, Science and Technology of Pharmaceutical Compounding (1999);Pickar, Dosage Calculations (1999); and Remington: The Science andPractice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott,Williams & Wilkins).

The therapeutically effective amount of a compound of the invention canbe initially estimated from cell culture assays. Target concentrationswill be those concentrations of active compound(s) that are capable ofachieving the therapeutic effect described herein, as measured using themethods described herein or known in the art.

Therapeutically effective amounts for use in humans can also bedetermined from animal models using known methods. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compound effectiveness and adjusting the dosage upwards ordownwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

A prophylactic or therapeutic treatment regimen is suitably one thatdoes not cause substantial toxicity and yet is effective to treat theclinical symptoms demonstrated by the particular patient. Thisdetermination of a dosage regimen is generally based upon an assessmentof the active compound by considering factors such as compound potency,relative bioavailability, patient body weight, presence and severity ofadverse side effects, preferred mode of administration and the toxicityprofile of the selected agent.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

Compounds

In certain embodiments the compound of formula (I) is of the formula(II), or a pharmaceutically acceptable salt thereof:

In certain embodiments the compound of formula (I) is of the formula(III), or a pharmaceutically acceptable salt thereof:

In certain embodiments the compound of formula (I) is of the formula(IV), or a pharmaceutically acceptable salt thereof:

In certain embodiments the compound of formula (I) is of the formula(V), or a pharmaceutically acceptable salt thereof:

In certain embodiments the compound of formula (I) is of the formula(VI), or a pharmaceutically acceptable salt thereof:

In certain embodiments the compound of formula (I) is of the formula(VII), or a pharmaceutically acceptable salt thereof:

Particular compounds of the invention include, for example, compounds offormulae (I), (II), (III), (IV), (V), (VI) or (VII), or apharmaceutically acceptable salt thereof, wherein, unless otherwisestated, each of R¹, R², R³, R⁴, A¹, A², B¹, B², X, X¹, a, b and n hasany of the meanings defined hereinbefore or in any one or more ofparagraphs (1) to (58) hereinafter:

(1) The group CX is —CHF₂ or —CF₃.(2) The group CX is —CF₃.(3) A¹ is CR¹.(4) A¹ is CR¹ and R¹ is selected from the group consisting of CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A1) and—C(O)NR^(A1)R^(B1).(5) A¹ is CR¹ and R¹ is selected from the group consisting of: H, CN,C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, alkyl-OH, —C₁₋₃ alkyl-OMe, —C(O)NH₂;—C(O)NHMe and —C(O)N(Me)₂.(6) A¹ is CR¹ and R¹ is selected from the group consisting of: CN, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, alkyl-OH, —C₁₋₃ alkyl-OMe, —C(O)NH₂; —C(O)NHMeand —C(O)N(Me)₂.(7) A¹ is CR¹ and R¹ is selected from the group consisting of: H, CN,methyl, ethyl, —CH₂F, —CH₂OH, —CH₂OMe, —C(O)NH₂; —C(O)NHMe and—C(O)N(Me)₂.(8) A¹ is CR¹ and R¹ is selected from the group consisting of: H, CN,methyl, —CH₂F and —CH₂OH (e.g. R¹ is selected from the group consistingof: H, CN, methyl and —CH₂F).(9) A¹ is CR¹ and R¹ is —CN.(10) A¹ is CR¹ and R¹ is methyl or ethyl, preferably methyl.(11) A¹ is CR¹ and R¹ is —CH₂F.(12) A¹ is CR¹ and R¹ is —CH₂OH.(13) A¹ is CR¹ and R¹ is H.

(14) A¹ is N.

(15) A¹ is N and A² is CR³.(16) A¹ is N, R² is methyl or ethyl, and A² is CH.(17) R² is selected from the group consisting of: C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A2) and —C(O)NR^(A2)R^(B2).(18) R² is selected from the group consisting of: H, C₁₋₄ alkyl, C₁₋₄haloalkyl and —C₁₋₄ alkyl-OR^(A2).(19) R² is selected from the group consisting of: H, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, alkyl-OH and —C₁₋₃alkyl-OMe.(20) R² is selected from the group consisting of: C₁₋₃ alkyl, C₁₋₃fluoroalkyl, —C₁₋₃ alkyl-OH and —C₁₋₃ alkyl-OMe.(21) R² is selected from the group consisting of: H, C₁₋₃ alkyl, —C₁₋₃alkyl-OH and —C₁₋₃ alkyl-OMe.(22) R² is selected from the group consisting of: H, methyl, ethyl,—CH₂OH and —CH₂OMe.(23) R² is selected from the group consisting of: H, methyl and —CH₂OH.(24) R² is selected from the group consisting of: methyl and —CH₂OH.

(25) R² is H. (26) A² is N.

(27) A² is N and A¹ is CR¹.(28) A² is N, A¹ is CR¹, and R¹ is as defined in any of (3) to (13)above.(29) A² is N, A¹ is CR¹, and R¹ is methyl or —CH₂F.(30) A² is CR³ and R³ is selected from the group consisting of: C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A3) and—C(O)NR^(A3)R^(B3).(31) A² is CR³ and R³ is selected from the group consisting of: C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OH and—C(O)NR^(A3)R^(B3)(32) A² is CR³ and R³ is selected from the group consisting of: H, C₁₋₃alkyl, C₁₋₃ haloalkyl, alkyl-OR^(A3) and —C(O)NR^(A3)R^(B3).(33) A² is CR³ and R³ is selected from the group consisting of: H, C₁₋₃alkyl, C₁₋₃ haloalkyl, alkyl-OH and —C(O)NR^(A3)R^(B3)(34) A² is CR³ and R³ is selected from the group consisting of: H, C₁₋₃alkyl, C₁₋₃ haloalkyl and —C₁₋₃ alkyl-OR^(A3).(35) A² is CR³ and R³ is selected from the group consisting of: H, C₁₋₃alkyl, C₁₋₃ haloalkyl and —C₁₋₃ alkyl-OH.(36) A² is CR³ and R³ is selected from the group consisting of: H, C₁₋₃fluoroalkyl and —C₁₋₃ alkyl-OH.(37) A² is CR³ and R³ is selected from the group consisting of: H, —CH₂Fand —CH₂OH.(38) A² is CR³ and R³ is H.

(39) B² is CH.

(40) B¹ and B² are both N.(41) B¹ is N and B² is CH.(42) B¹ and B² are both CH.

(43) R⁴ is F.

(44) n is 0 or 1.

(45) n is 0 or 1 and R⁴ is F.

(46) n is 0.

(47) n is 1 and R⁴ is F.

(48) X¹ is CH₂.

(49) X¹ is O.

(50) a+b is 1, 2 or 3.(51) a+b is 1 or 2.(52) The group of the formula:

is selected from the group consisting of:

for example a group selected from:

(53) The group of the formula:

is selected from:

(54) The group of the formula:

is

(55) The group of the formula:

is

(56) The group of the formula:

is selected from the group consisting of:

(57) The group of the formula:

is selected from the group consisting of:

(58) when A¹ is N, R² is C₁₋₄ alkyl or C₁₋₄ haloalkyl (e.g. R² is methylor ethyl).

In certain embodiments there is provided a compound of the formula (I)wherein:

A¹ is N or CR¹;A² is N or CR³;and wherein only a single one of A¹ and A² may be N;R¹ is selected from the group consisting of: H, CN, methyl, fluoromethyland hydroxymethyl;R² is selected from the group consisting of: H, methyl andhydroxymethyl;R³ is selected from H, fluoromethyl and hydroxymethyl;each X is F;

B¹ is CH or N; B² is CH;

X¹ is O or CH₂;a is an integer selected from 0, 1 or 2;b is an integer selected from 0, 1 or 2;a+b is 0, 1, 2 or 3; andn is 0;with the following provisos:R¹, R² and R³ are not all H;(ii) when A¹ is N, at least one of R² and R³ is methyl; and(iii) when A² is N, at least one of R¹ and R² is methyl(iv) when A¹ is CR¹, R¹ is hydroxymethyl and B¹ is N, then R² is not H.

Preferably in this embodiment the group of the formula:

is selected from:

In certain embodiments there is provided a compound of the formula (I)wherein B¹ is N; B² is CH; and R¹ is not H.

In certain embodiments there is provided a compound of the formula (I)wherein B¹ is N; B² is CH;

R¹ is selected from the group consisting of: CN, C₁₋₃ alkyl, C₁₋₃haloalkyl, alkyl-OH, —C₁₋₃ alkyl-OMe, —C(O)NH₂; —C(O)NHMe and—C(O)N(Me)₂; andR² is selected from any of (17) to (25) above. Preferably in thisembodiment n is 0.

In certain embodiments there is provided a compound of the formula (I)wherein B¹ is N; B² is CH;

R¹ is selected from the group consisting of: CN, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, alkyl-OH, and —C₁₋₃ alkyl-OMe; andR² is selected from the group consisting of: H, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, alkyl-OH and —C₁₋₃ alkyl-OMe. Preferably in this embodimentn is 0.

In certain embodiments there is provided a compound of the formula (I)wherein B¹ is N; B² is CH;

R¹ is selected from the group consisting of: CN, methyl and —CH₂F; andR² is selected from H and methyl.Preferably in this embodiment n is 0 or n is 1 and R⁴ is F, morepreferably n is 0.

In certain embodiments in the compounds of the formulae (I), (II),(III), (IV), (IV), (V), (VI) and (VII) n is 0.

In certain embodiments in the compound of formula (I) B¹ and B² are bothCH and n is 0.

In certain embodiments in the compounds of the formulae (I), (II),(III), (IV), (V), (VI) and (VII) n is 0 and B¹ is CH.

In certain embodiments in the compounds of the formulae (I), (II) and(III), n is 0 and the group of the formula:

is selected from:

Preferably in these embodiments B¹ and B² are CH.

In certain embodiments in the compound of the formula (IV) R¹ is not H

In certain embodiments in the compound of the formula (IV) R¹ is not H(for example R¹ is as defined in any of (4) to (12) above); and

A² is CH or N (preferably A² is CH).

In certain embodiments in the compound of the formula (IV) R¹ isselected from the group consisting of: CN, C₁₋₂ fluoroalkyl, —C₁₋₂alkyl-OR^(A1) and —C(O)NR^(A1)R^(B1);

R^(A1) and R^(B1) are each independently selected from the groupconsisting of: H, methyl and ethyl, preferably H and methyl; andA² is CH or N, preferably CH.

In certain embodiments in the compound of the formula (IV) R¹ isselected from the group consisting of: CN, C₁₋₂ fluoroalkyl, —C₁₋₂alkyl-OH and —C(O)NH(Me); and

A² is CH or N, preferably CH.

In certain embodiments in the compound of the formula (IV) R¹ isselected from the group consisting of: CN, fluoromethyl andhydroxymethyl; and

A² is CH or N, preferably CH.

In the above five embodiments of the compound of the formula (IV) n ispreferably 0. More preferably n is 0 and B¹ is CH.

In certain embodiments in the compound of the formula (V) R¹ and R² arenot H.

In certain embodiments in the compound of the formula (V) R¹ is selectedfrom the group consisting of: CN, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, —C₁₋₂alkyl-OR^(A1) and —C(O)NR^(A1)R^(B1);

R² is C₁₋₂ alkyl;R^(A1) and R^(B1) are each independently selected from the groupconsisting of: H, methyl and ethyl, preferably H and methyl; andA² is CH or N, preferably CH.

In certain embodiments in the compound of the formula (V) R¹ is selectedfrom the group consisting of: CN, C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, —C₁₋₂alkyl-OH and —C(O)NH(Me);

R² is C₁₋₂ alkyl;A² is CH or N, preferably CH.

In certain embodiments in the compound of the formula (V) R¹ is selectedfrom the group consisting of: CN, methyl, fluoromethyl andhydroxymethyl;

R² is C₁₋₂ alkyl;A² is CH or N, preferably CH.

In the above four embodiments of the compound of the formula (V) n ispreferably 0. More preferably n is 0 and B¹ is CH.

In certain embodiments in the compound of the formula (VI) A¹ isselected from N and CR¹ (preferably CR¹);

R¹ is selected from the group consisting of: CN, C₁₋₂ alkyl, C₁₋₂fluoroalkyl, —C₁₋₂ alkyl-OH and —C(O)NH(Me); and

A² is CH.

Preferably in this embodiment of the compound of the formula (VI) n is0. More preferably n is 0 and B¹ is CH.

In certain embodiments in the compound of the formula (VII) R² isselected from the group consisting of H and C₁₋₂ alkyl; and

A² is CH or N, preferably CH.

Preferably in this embodiment of the compound of the formula (VII) n is0. More preferably A² is CH, n is 0 and B¹ is CH.

In certain embodiments in the compound of the formula (VII) R² is H, A²is CH, n is 0 and B¹ is CH.

It may be that in any of the embodiments of the compounds of theformulae (I), (IV), (V), (VI) and (VII) herein a+b is 1, 2 or 3,preferably a+b is 1 or 2.

Preferably in any of the embodiments of the compounds of the formulae(I), (IV), (V), (VI) and (VII) herein, the group of the formula:

is selected from:

In certain embodiments in the compound of formula (V) the group of theformula:

is selected from the group consisting of:

Suitably in this embodiment A² is CH; and n is O.

Suitably in this embodiment A² is CH; n is 0 and B¹ is CH.

In another embodiment there is provided a compound of the formula (I)selected from:

Without wishing to be bound by theory, the compounds of the inventionare thought to potentiate AMPA receptors by acting as positiveallosteric modulators (PAMs) of the AMPA receptor. An “allostericmodulator” is an agent is an agent which indirectly modulates theeffects of an agonist or inverse agonist at a receptor. Allostericmodulators bind to a site distinct from that of the orthosteric agonistbinding site. Generally allosteric modulators induce a conformationalchange within the protein structure of the receptor. A “positiveallosteric modulator” (PAM) induces an amplification of the orthostericagonist's effect, either by enhancing the binding affinity or thefunctional efficacy of the orthosteric agonist for the target receptor.Accordingly, the compounds of the invention are expected to potentiatethe effect of AMPA receptors when endogenous glutamate is released. Thecompounds of the invention have little or no effect upon channelcurrents per se and are only able to enhance ion flux through thereceptor in the presence of the endogenous glutamate ligand.Accordingly, a compound of the invention may potentiate AMPA receptorsby, for example, (i) slowing the rate at which the receptor desensitizesin the continued presence of glutamate; and/or (ii) slowing the rate atwhich the receptor deactivates after removal of glutamate; and/or (iii)enhancing or prolonging glutamatergic synaptic currents, therebypromoting synaptic transmission and plasticity (e.g. long-termpotentiation (LTP) of synapses). Preferred compounds potentiate AMPAreceptor effects (e.g. enhancing cognition) without significantlycorrupting spatial and temporal information.

Compounds of the invention are thought to bind on the twofold axis ofthe GluA2 ligand binding domain (LBD) dimer which is formed by residuesthat act as ‘hinges’ between the two structural domains of each LBD.Modulators binding at this site may act to slow receptor deactivation bystabilizing the clamshell dimer in its closed cleft glutamate boundconformation and/or slow desensitization by stabilizing the dimerinterface (Ward et al., British Journal of Pharmacology, 2010, 160181-190).

Activation of the AMPA receptor by glutamate opens the pore of the ionchannel permitting the inward flow of sodium, resulting in thedepolarization of the neuronal membrane. This change in theintracellular charge releases the Mg²⁺ cation from theN-methyl-D-aspartate (NMDA) receptor channel, permitting passage of Ca²⁺through the NM DA receptor pore into the postsynaptic neurone andtriggering Ca²⁺-dependent signal transduction cascades, trafficking ofextra-synaptic AMPA receptors and high conductance GluA1 homomers to thepostsynaptic density, leading to the induction of forms of synapticplasticity (Passafaro et al.; Subunit-specific temporal and spatialpatterns of AMPA receptor exocytosis in hippocampal neurons. NatNeurosci 2001, 4, 917-926).

The potentiation of AMPA receptors by the compounds of the invention maybe assessed by measuring calcium ion influx via AMPA receptors uponexposure of the receptor to glutamate in the presence of a testcompound. One such assay is the calcium ion influx assay described inthe Examples using cells which express human GluR2 flip (GluA2 flip)AMPA receptor subunits which form functional homotetrameric AMPAreceptors. The GluA2 flip sub-units are highly expressed in cortical andsub-cortical brain tissue (Ward et al., 2010, ibid). The Examples showthat the compounds of the invention are potent potentiators of AMPAreceptors in the presence of the glutamate ligand.

The effects of a compound of the invention in-vitro could also bedetermined using human inducible pluripotent stem cell (iPSC)-derivedglutamate neurons (e.g. iCell® GlutaNeurons ex. Cellular DynamicsInternational) using multielectrode array electrophysiology. Ananalogous method is described in Dage et al., (pharmacologicalcharacterisation of ligand- and voltage-gated ion channels expressed inhuman iPSC-derived forebrain neurons, Psychopharmacology. 2014,231(6):1105-1124).

The compounds of the invention are expected to enhance cognition. Theeffect on cognition can be assessed in-vivo using known models ofbehavioural cognition. For example, a novel object recognition (NOR)model as described in Ennaceur et al., (Behav. Brain Res. 1988, 31,47-59). The test relies on a rat's natural tendency to explore noveltyand involves two trials. In the first (T1) the rat is exposed to twoidentical objects for a brief period of time (3 min). After a delay(inter trial interval: ITI), the rat is placed back in the chamber withone of the familiar objects it encountered in the first phase and anadditional novel object (T2). Rodents typically spend more timeexploring the novel object over the familiar object, which isinterpreted as reflecting the rodent's memory for the familiar objectand its desire to explore a novel object. Because the task relies on therodent's preference for novelty, it does not require any rule learningand hence no pre-training. Task difficulty can be increased byincreasing the delay between T1 and T2. In a variant of this methodmemory loss in the rat can be induced using a pharmacological agent, forexample sub-chronic phencyclidine, instead of the intertrial interval(ITI) time delay. Certain of the compounds exemplified herein have beentested in the NOR model and exhibited a minimum effective dose in theNOR test of less than 10 mg/kg, when administered orally.

Suitably the compounds of the invention provide a wide therapeuticwindow between the desirable pro-cognitive effects and undesirableside-effects, particularly pro-convulsive effects which may result fromover-activation of AMPA receptors.

The potential for a compound to induce convulsive effects may bedetermined using a variety of models. For example, in-vitropro-convulsant liability may be assessed using rodent neuronalelectrophysiology hippocampus slices to assess potentially convulsiveeffects of a compound at different concentrations. The liability of acompound to induce repetitive firing being an in-vitro surrogate ofconvulsant activity.

Potential pro-convulsant effects in-vivo may be assessed using forexample a maximum electroshock threshold (MEST) test. In the MEST test,corneal application of electrical current (CC of approximately 60-70 mA,0.1 ms duration) in the rat induces tonic and full tonic-clonicseizures. In order to assess the potential of a compound to reduceseizure threshold activity, rats are pre-treated with compound, salinevehicle, or picrotoxin as a positive control 30 min before testing.Models for assessing the convulsant effects of compounds are known anddescribed in, for example Ward et al., J. Med. Chem. 2011, 54, 78-94,and Loscher et al., Epilepsy Res. 1991, 8: 79-84.

Suitably the compound of the invention does not show any pro-convulsantactivity in the MEST test at doses which are at least 50 times greaterthan the minimum efficacious dose in the NOR test. For example, nopro-convulsive effects are observed in the MEST test at doses which aregreater than 75 times, or preferably greater than 100 times the minimumefficacious dose in the NOR test.

The compounds of the invention suitably have a favourable drugmetabolism and pharmacokinetic (DMPK) profile, for example lowclearance, high oral bioavailability, high brain penetration and ahalf-life providing a reasonable duration of action following dosing ofthe compound.

Suitably the compounds of the invention exhibit a low in-vitro intrinsicclearance (CLi) in the presence of rat, dog and/or human livermicrosomes. For example, compounds of the invention preferably have aCLi of less than 100 μL/min/kg in rat and human microsomes. The CLi canbe measured using known methods, such as those illustrated in theExamples.

Human P-glycoprotein (P-gp, MDR1) is highly expressed in the blood brainbarrier and poses a barrier to brain penetration for P-gp substrates.Compounds with a high P-gp efflux liability may exhibit low penetrationof the blood-brain barrier resulting in low, possibly sub-therapeutic,brain concentration of the compound.

Suitably compounds of the invention exhibit an efflux ratio of less than5, preferably less than 2 when measured in an efflux assay usingMadin-Darby canine kidney (MDCK) cell line transfected with human MDR1as described in Feng et al., Drug Metabolism and Disposition, TheAmerican Society for Pharmacology and Experimental Therapeutics, Vol 36(2), 2008, 268-275. Compounds of the invention suitably exhibit a highmembrane permeability in, for example the PAMPA, assay described in Fenget al.

The biological properties of the compounds may be assessed using themethods described herein including the Examples. The properties of thecompounds may also be assessed using the methodology and screeningcascade described in Ward et al., 2010 ibid, for example FIG. 6 therein.

Pharmaceutical Compositions

In accordance with another aspect, the present invention provides apharmaceutical composition comprising a compound of the invention and apharmaceutically acceptable excipient.

Conventional procedures for the selection and preparation of suitablepharmaceutical compositions are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988; and Remington: The Science and Practice ofPharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing). Suitably the compound of the invention is administered orally,for example in the form of a tablet, capsule, granule or powder dosageform.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more fillers, binders, colouring, sweetening, flavouringand/or preservative agents. Pharmaceutical excipients suitable for thepreparation of dosage forms are well known, for example as described inthe Handbook of Pharmaceutical Excipients, Seventh Edition, Rowe et al.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients, which may vary from about 5 to about 98 percent byweight of the total composition.

Therapeutic Uses and Applications

The Background section herein provides information on the potentiationof AMPA receptors and the potential therapeutic benefits expected toarise therefrom. It is to be understood that this disclosure is alsoconsidered to be part of the Detailed Description of the Invention.

The compounds of the invention potentiate AMPA receptors. Accordingly, acompound of the present invention for use in the treatment of acondition which is modulated by an AMPA receptor.

Suitably the compound of the invention is for use in the treatment of acondition in which AMPA receptor function is impaired. Accordingly, thecompound of the invention may be for use in the treatment of a conditionin which potentiation of an AMPA receptor is beneficial.

Suitably a compound of the invention is for use in the treatment of acondition in which glutamatergic neurotransmission is dysfunctional.Accordingly, it may be that a compound of the invention is for use inthe treatment of a neurological or psychiatric condition associated withglutamate dysfunction. Such glutamatergic disorders are known andinclude one or more of the conditions described herein.

It may be that the compound of the invention is for use in the treatmentof cognitive dysfunction. Cognitive dysfunction may arise as a resultof, for example, ageing or as an effect of a disease or condition. Inparticular a compound of the invention may be for use in the treatmentof cognitive dysfunction associated with a neuropsychiatric disease. Itmay be that a compound of the invention is for use in the treatment ofconditions where long-term potentiation (LTP or synaptic plasticity) hasbeen impaired, for example in the treatment of Huntington's disease,e.g. to improve synaptic plasticity and/or memory in a subject withHuntington's disease.

It may be that the compound of the invention is for use in the treatmentor prevention central nervous system (CNS) disorders associated with analteration in one or more of cognitive function, synaptic plasticity, oran imbalance in excitatory/inhibitory neurotransmission.

It may be that the compound of the invention is for use in the treatmentof cognitive dysfunction associated with a neurological disorder or aneuropsychiatric condition, for example cognitive dysfunction associatedwith a glutamatergic disorder.

Reference to “cognitive dysfunction” or “cognitive impairment” are usedinterchangeably herein and refer to a loss or impairment of intellectualfunctions, including but not limited to one or more of memory,reasoning, problem solving, verbal recall, concentration, attention,speed of processing, executive function, social cognition, verballearning, visual learning and perception.

A compound of the invention may be for use in the treatment of cognitiveimpairment, for example impairment of attention, orientation, memory,memory disorders, amnesia, amnesic disorders, age related cognitiveimpairment, age-associated memory impairment, language function learningdisorders and attention disorders.

AMPA receptor modulators have been shown to be beneficial in preclinicalmodels of other diseases, for example, depressive disorders (Quirk etal.: a novel positive allosteric modulator of AMPA receptors; CNS DrugRev., 2002, 8, 255-282; and O'Neill et al., AMPA receptor potentiators:application for depression and Parkinson's disease; Curr. Drug Targets,2007, 8, 603-620); Huntington's disease (Simmons et al., Up-regulatingBDNF with an ampakine rescues synaptic plasticity and memory inHuntington's disease knockin mice. Proc. Natl. Acad. Sci. USA, 2009,106, 4906-4911); stroke (Dicou et al., Positive allosteric modulators ofAMPA receptors are neuroprotective against lesions induced by an NMDAagonist in neonatal mouse brain. Br. Res, 2003, 970, 221-225) andParkinson's disease (Bloss et al., Behavioural and biological effects ofchronic S18986, a positive AMPA receptor modulator, during aging. ExpNeurol., 2008, 210: 109-117).

A compound of the invention may be for use in the treatment of one ormore of the conditions listed below, for example those listed in the 5bullet points below. In some embodiments a compound of the invention maybe for use in the treatment of one or more of enhancing cognitivefunction and/or synaptic plasticity and/or an imbalance inexcitatory/inhibitory neurotransmission cognitive impairment associatedwith one or more of the following conditions:

-   -   psychosis and psychotic disorders, for example schizophrenia,        schizo-affective disorder, schizophreniform diseases, brief        reactive psychosis, child onset schizophrenia,        “schizophrenia-spectrum” disorders such as schizoid or        schizotypal personality disorders, acute psychosis, alcohol        psychosis, drug-induced psychosis, autism (including Asperger's        disorder and Rett's disorder), delirium, mania (including acute        mania), manic depressive psychosis, hallucination, endogenous        psychosis, organic psychosyndrome, paranoid and delusional        disorders, puerperal psychosis, and psychosis associated with        neurodegenerative diseases such as Alzheimer's disease;    -   substance related disorders; for example, selected from        substance abuse substance dependence, substance intoxication,        substance withdrawal, alcohol-related disorders, amphetamine        related disorders, cannabis related disorders, cocaine related        disorders, and nicotine-related disorders, opioid related        disorders (for example opioid dependence, opioid abuse, opioid        intoxication, opioid withdrawal or opioid induced psychotic        disorder);    -   neurodegenerative diseases, for example selected from        Alzheimer's disease; amyotrophic lateral sclerosis; motor        neurone disease; motor disorders; Parkinson's disease; dementia        in Parkinson's disease; dementia in Huntington's disease;        neuroleptic-induced Parkinsonism and tardive dyskinesias;        neurodegeneration following stroke, cardiac arrest, pulmonary        bypass, traumatic brain injury, spinal cord injury or perinatal        hypoxia; and demyelinating diseases such as multiple sclerosis        and amyotrophic lateral sclerosis;    -   depression, for example bipolar depression (including type I and        type II), unipolar depression, single or recurrent major        depressive episodes with or without psychotic features,        catatonic features, melancholic features, atypical features        (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum        onset, seasonal affective disorder and dysthymia,        depression-related anxiety, psychotic depression; and    -   a disorder selected from post-traumatic stress syndrome,        attention deficit disorder, attention deficit hyperactivity        disorder, drug-induced disorders (for example disorders induced        by phencyclidine, ketamine, opiates, cannabis, amphetamines,        dissociative anaesthetics, amphetamine, cocaine and other        psychostimulants); Huntingdon's chorea; tardive dyskinesia;        dystonia; myoclonus; spasticity; obesity; stroke; sexual        dysfunction; sleep disorders including narcolepsy and other        conditions resulting from sleep disorder; migraine; trigeminal        neuralgia, hearing loss; tinnitus, ocular damage, retinopathy,        macular degeneration; and pain (including acute and chronic        pain, severe pain, intractable pain, neuropathic pain, and        post-traumatic pain).

In embodiments a compound of the invention is for use in the treatmentof cognitive impairment associated with any of the conditions listedabove. For example a compound of the invention may be for use in thetreatment of cognitive impairment associated with or resulting fromstroke, Alzheimer's disease, Huntington's disease, Pick disease,Aids-related dementia, Multiinfarct dementia, alcoholic dementia,hypothyroidism-related dementia, and dementia associated to otherdegenerative disorders such as cerebellar atrophy and amyotrophiclateral sclerosis, delirium, depression trauma, head trauma, aging,neurodegeneration, drug-induced states, neurotoxic agents, autism,Down's syndrome, psychosis, post-electroconvulsive treatment; anxietydisorders (including generalised anxiety disorder, social anxietydisorder, agitation, tension, social or emotional withdrawal inpsychotic patients, panic disorder and obsessive compulsive disorder),substance-induced persisting dementia, substance-induced persistingamnesic disorder or substance induced psychotic disorder.

Accordingly one embodiment provides a compound of the invention for usein the treatment of a neurological or neuropsychiatric disease orcondition. For example, a compound of the invention may be for use inthe treatment of Alzheimer's disease, Parkinson's disease, Huntington'sdisease, Amyotrophic Lateral Sclerosis, schizophrenia,obsessive-compulsive disorder, addiction and mood disorders (includingmajor depressive disorders and bipolar disorder). Particularly thecompound of the invention may be for use in the treatment of cognitivedysfunction associated with any such condition.

In a particular embodiment there is provided a compound of the inventionfor use in the treatment of schizophrenia. For example, a compound ofthe invention may be for use in the treatment a subtype of schizophreniaselected from paranoid type, disorganised type, catatonic type,undifferentiated type and residual type schizophrenia.

The assessment of the cognitive effects of the compounds in humanssuffering from schizophrenia can be assessed using known methods, forexample using the MATRICS Consensus Cognitive Battery (MCCB) is astandardized battery for use with adults with schizophrenia (Buchanan etal., A summary of the FDA-NIMH-MATRICS workshop on clinical trial designfor neurocognitive drugs for schizophrenia. Schizophr. Bull. 2005;31(1):5-19).

Depressive Disorders

As disclosed in the Background section ketamine has been shown to beeffective in the treatment of depression and that the effects ofketamine are attributable to AMPA receptor potentiation by a metaboliteof ketamine (see e.g. Zanos 2016 ibid). Accordingly, compounds of theinvention are expected to be useful in the treatment of depressivedisorders, particularly major depressive disorders.

Major depressive disorder (MDD) (also known as clinical depression,major depression, unipolar depression, unipolar disorder or recurrentdepression) is defined in the International Statistical Classificationof Diseases and Related Health Problems (ICD-10) as a mental disordercharacterized by a pervasive and persistent low mood that is accompaniedby low self-esteem and by a loss of interest or pleasure in normallyenjoyable activities. Depressive disorders also include milder forms ofdepression, including for example mood-disorders. The depressivedisorder may be a hereditary depressive disorder and/or a depressivedisorder induced by reaction to environmental or biological stressfactors, for example, acute life events, childhood exposure to adversityor stress caused by the signs or symptoms of a medical condition, forexample depression that arises from pain in a subject. Depressivedisorders may also be associated with or caused by other medicalconditions, for example, psychotic disorders, cognitive disorders,eating disorders, anxiety disorders or personality disorders. Thedepressive disorder may be an acute depressive disorder, a recurrentdepressive disorder or a chronic depressive disorder.

In embodiments a compound of the invention is for use in the treatmentof a depressive disorder selected from major depressive disorder,dysthymic disorder (persistent depressive disorder), atypicaldepression, melancholic depression, psychotic depression, catatonicdepression, postpartum depression (PPD), premenstrual syndrome,premenstrual dysphoric disorder (PMDD), seasonal affective disorder(SAD), double depression, depressive personality disorder (DPD),recurrent brief depression (RBD), minor depressive disorder, bipolardisorder, bipolar depression, substance/medication-induced depressivedisorder (including alcohol-induced and benzodiazepine-induced),post-schizophrenic depression and a depressive disorder caused by orassociated with another medical condition (e.g. depressions caused by orassociated with a dementia, metabolic disorder, multiple sclerosis,cancer, chronic pain, chemotherapy and/or chronic stress. In someembodiments a compound of the invention is for use in the treatment of adepressive disorder which has an associated anxious component or anxietydisorder. For example, the treatment of a depressive disorder describedherein with an associated anxiety disorder as described herein (e.g.selected from a panic disorder, panic disorder with agoraphobia, asocial phobia, a specific phobia (e.g. an animal or environmentalphobia), post-traumatic distress disorder, an acute stress disorder, anobsessive compulsive disorder (OCD) and panic attacks).

In some embodiments a compound of the invention is for use in thetreatment of a mood disorder. Mood disorders are conditions in which apatient's mood changes to depression (often with associated anxiety)and/or to elation. The mood disorders may be acute or recurrent and areoften triggered by stressful events or situations. Examples of mooddisorders include, manic episodes (e.g. hypomania, mania with psychoticsymptoms or mania without psychotic symptoms); a bipolar affectivedisorder (e.g. manic depression or a manic depressive illness, psychosisor reaction); a depressive episode (e.g. mild, moderate or severedepressive episode); a recurrent depressive disorder; a persistent mooddisorders (e.g. cyclothymia or dysthymia); or anhedonia.

Various symptoms are associated with depressive disorders and mooddisorders such as MDD, for example, persistent anxious or sad feelings,feelings of helplessness, hopelessness, pessimism, worthlessness, lowenergy, restlessness, irritability, fatigue, loss of interest inpleasurable activities or hobbies, excessive sleeping, overeating,appetite loss, insomnia, thoughts of suicide, and suicide attempts. Thepresence, severity, frequency, and duration of these symptoms vary on acase to case basis. In some embodiments, a patient may have at leastone, at least two, at least three, at least four, or at least five ofthese symptoms.

The effect of a compound of the invention on a depressive disorder ormood disorder may be assessed using known methods. Suitable in-vivomodels of depression include for example the animal models described inZanos et al 2016 ibid including the learned helplessness assay andfemale urine sniffing test after chronic mild stress. In human theeffect of a compound on depressive or mood disorders may be assessed by,for example, an improvement in a patient's symptoms using a suitableclinical scoring or rating system such as a depression symptoms ratingscale. Reference to a “depression symptoms rating scale” refers to anyone of a number of standardized questionnaires, clinical instruments, orsymptom inventories utilized to measure symptoms and symptom severity indepressive disorders. Such rating scales are often used in clinicalstudies to define treatment outcomes, based on changes from the study'sentry point(s) to endpoint(s). Examples of depression symptoms ratingscales include, but are not limited to, The Quick Inventory ofDepressive-Symptomatology Self-Report (QIDS-SRi6), the 17-Item HamiltonRating Scale of Depression (HRSDn), the 30-Item Inventory of DepressiveSymptomatology (IDS-C30), The Montgomery-Åsberg Depression Rating Scale(MADRS), or The Beck's Depression Scale Inventory. Such ratings scalesmay involve patient self-report or be clinician rated.

Generally, a 50% or greater reduction in a depression ratings scalescore over the course of a clinical trial (starting point to endpoint)is often considered to be a favourable response for most depressionsymptoms rating scales, although lower % reductions may provide abenefit and are contemplated herein. Generally, “remission” in clinicalstudies of depression refers to achieving at, or below, a particularnumerical rating score on a depression symptoms rating scale (forinstance, less than or equal to 7 on the HRSD17; or less than or equalto 5 on the QIDS-SRie; or less than or equal to 10 on the MADRS).

In some embodiments, a compound of the invention is for use in thetreatment of a depressive condition or mood disorder (e.g. as describedherein), wherein the compound provides a rapid effect on the depressivecondition or mood disorder. For example, wherein the compound of theinvention provides a clinically meaningful effect on the condition ordisorder within 1, 2, 3, 4, 6, 8, 12, 24 or 36 hours afteradministration of the compound to a subject. The clinical effect of thecompound may be assessed using a suitable depression symptoms ratingscale.

In some embodiments, a compound of the invention is for use in thetreatment of a depressive condition or mood disorder (e.g. as describedherein), wherein the compound provides a sustained effect on thecondition or disorder following administration of the compound tosubject. For example, wherein the compound provides a clinicallymeaningful effect on the condition or disorder which persists 1 week, 2weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks or 12 weeks afteradministration of the compound to a subject. The clinical effect of thecompound may be assessed using a suitable depression symptoms ratingscale.

In some embodiments a compound of the invention is for use in thetreatment of a treatment resistant depressive disorder. In thisembodiment the depressive disorder may be any of the depressivedisorders described herein.

Treatment resistant depression (TRD), sometimes referred to asrefractory depression, occurs in subjects suffering from a depressivedisorder who are non-responsive or poorly responsive to one or more,standard pharmacological treatments for the depressive disorder.Examples of standard pharmacological treatments for the depressivedisorder including tricyclic antidepressants, monoamine oxidaseinhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs),serotonin-norepinephrine reuptake inhibitors (SNRIs), ketamine,esketamine or other NMDA modulators, double and triple uptakeinhibitors, anxiolytic drugs, atypical anti-depressants and/oranti-psychotic treatments. TRD may also occur in subjects with adepressive disorder who are poorly responsive or non-responsive to oneor more non-pharmacological treatments of the depressive disorder (e.g.psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/ortranscranial magnetic stimulation).

A treatment resistant-subject may be identified as one who fails toexperience alleviation of one or more symptoms of depression (e.g.persistent anxious or sad feelings, feelings of helplessness,hopelessness, pessimism) despite undergoing one or more, preferably 2 ormore standard pharmacological or non-pharmacological treatment, such astwo, three or four different antidepressant drugs. A treatment-resistantsubject may also a subject that does not experience a 50% reduction indepressive symptoms after 2 courses of a standard pharmacologicaltreatment for the depressive disorder.

Suicide Ideation

In some embodiments, a compound of the invention is for use in thetreatment of suicide ideation. Suicidal behaviour is one of the leadingcauses of injury and death worldwide. Suicide ideation, or suicidalthoughts, is often association with or caused by depressive disordersand mood disorders. Accordingly, in certain embodiments there isprovided a compound of the invention for use in the treatment orprevention of suicide ideation. It may be that a compound of theinvention is for use in the treatment or prevention of suicide ideationin a subject with a depressive disorder or a mood disorder. Examples ofdepressive conditions or mood disorders are as described herein.

The effects of a compound of the invention may be assessed using asuitable clinical scoring system, for example a suitable suicidalideation rating scale for the measurement of the severity of suicideideation. Such suicidal ideation symptoms rating scales include, but arenot limited to, Scale for Suicidal Ideation (SSI), the Suicide StatusForm (SSF), or the Columbia Suicide Severity Rating Scale (C-SSRS).

Anxiety

In embodiments, a compound of the invention is for use in the treatmentof an anxiety disorder. Anxiety is a feeling of apprehension or fearthat lingers due to an individual's perception of persistent andunrelenting stress. Anxiety is typically accompanied by various physicalsymptoms including twitching, trembling, muscle tension, headaches,sweating (e.g., night sweats), dry mouth, or difficulty swallowing. Somepeople also report dizziness, a rapid or irregular heart rate, shortnessof breath, increased rate of respiration, fatigue, nausea, diarrhoea, orfrequent need to urinate when they are anxious. Fatigue, irritable mood,sleeping difficulties, decreased concentration, sexual problems, ornightmares are also common. Some people are more sensitive to stress andare thus more likely to develop anxiety disorders. The propensity tosuccumb to anxiety attacks may be due to genetic predisposition or byprevious (e.g. childhood) exposure to certain stresses. Anxiety may alsobe induced by or associated with medical conditions, for example pain,especially in patients suffering with chronic pain.

Examples of anxiety disorders include separation anxiety disorder,selective mutism, specific phobia, social anxiety disorder (socialphobia), panic disorder, panic attack, agoraphobia, post-traumaticstress disorders (PTSD), generalized anxiety disorder,substance/medication-induced anxiety disorder, anxiety disorder due toanother medical disorder (e.g. depression), other specified anxietydisorder, or unspecified anxiety disorder. As mentioned above theanxiety disorder may be associated with or be caused by a depressivedisorder.

The effect of a compound if the invention in the treatment of an anxietydisorder may be assessed using a suitable anxiety symptom rating scale.Such scales are well-known and include, for example standardizedquestionnaires, clinical instruments, or symptom inventories utilized tomeasure symptoms and symptom severity in anxiety. Examples of anxietysymptoms rating scales include, but are not limited to, State-TraitAnxiety Inventory (STAI), the Hamilton Anxiety Rating Scale (HAM-A), theBeck Anxiety Inventory (BAI), and the Hospital Anxiety and DepressionScale-Anxiety (HADS-A). Such ratings scales may involve patientself-reporting or be clinician rated. Generally, a 50% or greaterreduction in an anxiety ratings scale score over the course of aclinical trial (starting point to endpoint) is typically considered afavourable response, although lower reductions may also be beneficialand are contemplated.

The effects of a compound of the invention in the treatment of adepressive disorders, mood disorders and anxiety disorders may also beassessed using suitable pre-clinical models. For example, in a forcedswim test in rodent; a novelty-suppressed feeding model, a learnedhelplessness model or a chronic mild stress and social interactionmodel. Such models are well-known and described in for example, Wang etal The Recent Progress in animal models of depression Prog.Neuro-Psychopharm. Biol Psych. 2017 vol. 77, 99-109; Duman, Vit. Horm.2010 vol. 82, 1-21 or WO 2017/165877.

Respiratory Depression

AMPA receptor potentiators have been found to be useful in the treatmentof respiratory depression in preclinical models (Dai et al; Abrain-targeted ampakine compound protects against opioid-inducedrespiratory depression. Eur. J. Pharmacol, 2017, 809:122-9).Accordingly, in another embodiment there is provided a compound of theinvention for use in the treatment or prevention of respiratorydepression in a subject. For example, a compound of the invention may befor use in the treatment of respiratory depression wherein therespiratory depression is associated with the effect of alcohol, anopiate, an opioid (e.g. fentanyl), or a barbiturate on the subject. Inanother embodiment a compound of the invention is for use in thetreatment or prevention of respiratory depression associated with acondition associated with central sleep apnea, stroke-induced centralsleep apnea, obstructive, sleep apnea resulting from Parkinson'sdisease, congenital hypoventilation syndrome, sudden infant deathsyndrome, Retts syndrome, Cheney-Stokes respiration, Ondines Curse,spinal muscular atrophy, amyotrophic lateral sclerosis, Prader-Willi'ssyndrome, spinal cord injury, traumatic brain injury or drowning.

Also provided is a method of treating any of the foregoing conditions ina subject in need thereof by administering an effective amount of acompound of the invention to the subject.

Also provided in the use of a compound of the invention for themanufacture of a medicament for the any of the foregoing conditions.

An effective amount of a compound of the present invention for use intherapy of a condition is an amount sufficient to symptomaticallyrelieve in a subject, particularly a human, the symptoms of thecondition or to slow the progression of the condition.

Reference to a “subject” or “patient” herein refers to, for example awarm-blooded mammal, for example a human, non-human primate, cow, horse,pig, goat, sheep, dog, cat, rabbit, mouse or rat. Preferably the subjectis a human.

The size of the dose for therapeutic or prophylactic purposes of acompound of the invention will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well-known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, a daily dose selected from 0.001 mg/kg to 20 mg/kg,0.005 mg/kg to 15 mg/kg or 0.01 mg/kg to 10 mg/kg body weight isreceived, given if required in divided doses. In general, lower doseswill be administered when a parenteral route is employed. Thus, forexample, for intravenous or intraperitoneal administration, a dose inthe range, for example, 0.001 mg/kg to 1 mg/kg body weight willgenerally be used. The daily dose administered orally may be, forexample a total daily dose selected from 0.1 mg to 1000 mg, 0.5 mg to1000 mg, 1 mg to 500 mg or 1 mg to 250 mg. Typically, unit dosage formswill contain about 0.1 mg to 1000 mg, preferably about 0.5 mg to 500 mgof a compound of this invention.

Combinations

The compound of the invention can be administered alone or can beco-administered together with another therapeutic agent to a subject.The compounds of the invention can be used in co-administered with oneor more other active drugs known to be useful in treating a disease(e.g. a drug useful in the treatment of one of the diseases orconditions described herein such as a CNS condition).

By “co-administer” it is meant that a compound of the invention isadministered at the same time, prior to, or after the administration ofone or more additional therapeutic agent. Co-administration is meant toinclude simultaneous or sequential administration of the compound andthe additional therapeutic agent. Thus, the compound of the inventioncan be combined, when desired, with other therapeutic agents. Forsimultaneous administration, the compound of the invention and thetherapeutic agent may comprise a single pharmaceutical composition.Alternatively, the compound of the invention and the additionaltherapeutic agent may be comprised in two separate pharmaceuticalcompositions, which may be administered to the subject simultaneously orsequentially.

The compound of the invention and the one or more additional therapeuticagent may be administered to the subject using the same route ofadministration or by different routes of administration. For example,the compound of the invention and additional therapeutic agent may beadministered orally as a single pharmaceutical composition or as twoseparate compositions. Alternatively, the compound of the invention maybe administered to the subject orally and the therapeutic agent may beadministered by a different route of administration, e.g. parenterally.The administrations to the subject may occur substantiallysimultaneously or sequentially.

Co-administration includes administering one active agent within 0.5, 1,2, 4, 6, 8, 10, 12, 16, 20, 24, 48 hours or 1 week of a second activeagent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.

Additional Therapeutic Agent

The additional therapeutic agent may be any therapeutic agent suitablefor use in the treatment or prophylaxis of any of the conditionsdescribed herein. For example, when the compound of the invention is foruse in the treatment of a neurological, psychiatric condition,depressive disorder or mood disorder, the compound of the invention maybe co-administered with one or more additional therapeutic agentsselected from include antidepressants, antipsychotics, Alzheimer's drugsand anti-anxiety agents.

Accordingly, a compound of the invention may be co-administered with oneor more additional therapeutic agents selected from:

typical antipsychotics, for example chlorpromazine, thioridazine,mesoridazine, fluphenazine, perphenazine, prochlorperazine,trifluoperazine, thiothixine, haloperidol, molindone or loxapine;atypical antipsychotics, for example clozapine, olanzapine, risperidone,quetiapine, aripiprazole, ziprasidone, amisulpride, ziprasidone,paliperidone or bifeprunox;anticholinergics, for example benztropine, biperiden, procyclidine ortrihexyphenidyl;nicotine acetylcholine agonists, for example ispronicline, vareniclineand MEM 3454;cholinesterase inhibitors, for example donepezil and galantamineantihistamines, for example diphenhydramine;dopaminergics, for example amantadine;serotonin reuptake inhibitors, for example citalopram, escitalopram,fluoxetine, fluvoxamine, paroxetine, sertraline or venlafaxine;dual serotonin/noradrenaline reuptake inhibitors (SNRIs), for examplevenlafaxine, desvenlafaxine, duloxetine, milnacipran or levomilnacipran;triple reuptake inhibitors (serotonin, norepinephrine, dopamine reuptakeinhibitors, SNDRIs), for example, mazindol, nefazodone or sibutramine;noradrenaline (norepinephrine) reuptake inhibitors, for examplereboxetine;NK-1 receptor antagonists, for example aprepitant or maropitant,corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists;tricyclic antidepressants, for example amitriptyline, clomipramine,imipramine, maprotiline, nortriptyline or trimipramine, doxepin,trimipramine, dothiepin, butriptyline, iprindole, lofepramine,nortriptyline, protriptyline, amoxapine or desipramine;monoamine oxidase inhibitors, for example isocarboxazid, moclobemide,phenelzine, selegiline, or tranylcypromine;atypical anti-depressants, for example bupropion, lithium, nefazodone,trazodone or viloxazine;other antidepressants, for example bupropion, mianserin, mirtazapine ortrazodone;anxiolytics, for example benzodiazepines (e.g. alprazolam or lorazepamand others below), barbiturates (e.g. secobarbital, pentobarbital,butabarbital, phenobarbital, or amobarbital);cognitive enhancers, for example cholinesterase inhibitors (such astacrine, donepezil, rivastigmine or galantamine;stimulants, for example methylphenidate, amphetamine formulations orpemoline;mood stabilisers, for example lithium, sodium valproate, valproic acid,divalproex, carbamazepine, lamotrigine, gabapentin, topiramate ortiagabine;NMDA receptor antagonists, for example memantine, ketamine andesketamine;benzodiazepines, for example alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam or prazepam; and5-HT1A receptor agonists or antagonists, for example buspirone,flesinoxan, gepirone and ipsapirone.

According to another aspect of the invention there is provided acompound of the invention and another therapeutic agent for use in theconjoint treatment of a condition which is modulated by an AMPAreceptor.

Co-administration of a compound of the invention with anothertherapeutic agent may be beneficial in preventing or reducing negativeside effects associated with the other therapeutic agent. For example,certain therapeutic agents may affect cognitive function in a subject.Accordingly, a further aspect of the invention provides a compound ofthe invention for use in the treatment of cognitive dysfunctionresulting from the administration of another therapeutic agent to asubject.

In these last two embodiments the therapeutic agent may be any of thetherapeutic agents other than the compound of the invention describedherein, for example an anti-psychotic agent.

In a particular embodiment there is provided a compound of the inventionand another therapeutic agent for use in the conjoint treatment ofschizophrenia, wherein the other therapeutic agent is a typicalantipsychotic (for example chlorpromazine, thioridazine, mesoridazine,fluphenazine, perphenazine, prochlorperazine, trifluoperazine,thiothixine, haloperidol, molindone or loxapine) or an atypicalantipsychotic (for example clozapine, olanzapine, risperidone,quetiapine, aripiprazole, ziprasidone, amisulpride, ziprasidone,paliperidone, bifeprunox or talnetant). In this embodiment the conjoinedtreatment provides a treatment of cognitive impairment associated withschizophrenia.

In another embodiment there is provided a compound of the invention andan anti-depressant for use in the conjoint treatment of a depressivecondition (e.g. a major depressive disorder). The anti-depressant may beany anti-depressant other than an AMPA receptor modulator of theinvention. For example, a compound of the invention may be for use withan anti-depressant in the conjoined treatment of a depressive disorder,wherein the anti-depressant is selected from a tricyclic antidepressant,a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor,a serotonin-norepinephrine reuptake inhibitor, an NMDA modulator, adouble or triple uptake inhibitor, an anxiolytic drug and an atypicalanti-depressant.

Also contemplated is a compound of the invention and anon-pharmacological treatment of a depressive condition for use in theconjoint treatment of a depressive condition (e.g. a major depressivedisorder). The non-pharmacological treatment of a depressive conditionmay be, for example psychotherapy, electroconvulsive therapy, vagusnerve stimulation and/or transcranial magnetic stimulation)

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

Synthesis

The skilled person will appreciate that adaptation of methods known inthe art could be applied in the manufacture of the compounds of thepresent invention.

For example, the skilled person will be immediately familiar withstandard textbooks such as “Comprehensive Organic Transformations—AGuide to Functional Group Transformations”, RC Larock, Wiley-VCH (1999or later editions), “March's Advanced Organic Chemistry—Reactions,Mechanisms and Structure”, MB Smith, J. March, Wiley, (5th edition orlater) “Advanced Organic Chemistry, Part B, Reactions and Synthesis”, FA Carey, R J Sundberg, Kluwer Academic/Plenum Publications, (2001 orlater editions), “Organic Synthesis—The Disconnection Approach”, SWarren (Wiley), (1982 or later editions), “Designing Organic Syntheses”S Warren (Wiley) (1983 or later editions), “Guidebook To OrganicSynthesis” R K Mackie and D M Smith (Longman) (1982 or later editions),etc., and the references therein as a guide.

The skilled chemist will exercise judgement and skill as to the mostefficient sequence of reactions for synthesis of a given target compoundand will employ protecting groups as necessary. This will depend interalia on factors such as the nature of other functional groups present ina particular substrate. Clearly, the type of chemistry involved willinfluence the choice of reagent that is used in the said syntheticsteps, the need, and type, of protecting groups that are employed, andthe sequence for accomplishing the protection/deprotection steps. Theseand other reaction parameters will be evident to the skilled person byreference to standard textbooks and to the examples provided herein.

Sensitive functional groups may need to be protected and deprotectedduring synthesis of a compound of the invention. This may be achieved byconventional methods, for example as described in “Protective Groups inOrganic Synthesis” by T W Greene and P G M Wuts, John Wiley & Sons Inc(1999), and references therein.

Compounds of the formula (I) may be prepared by coupling a compound ofthe formula (VIII) with a compound of the formula (IX):

wherein:Lg¹ is halo, for example Cl;X² is a boronic acid or an ester thereof;A¹, A², R², R⁴, B¹, B², X, X¹, n, a and b are as defined herein.

The coupling reaction is suitably carried out as a Suzuki couplingreaction in the presence of a suitable catalyst (for example a palladiumor nickel catalyst) and a suitable base (e.g. an alkali metal carbonate,phosphate, alkoxide or hydroxide, or an organic amine).

The preparation of representative compounds are illustrated in Schemes 1to 6 below.

Reaction-(i) Reaction-(ii) Boronic Yield Yield ester Ar-Cl Product (%)Product (%) 8 17 32 54 49 49 8 21 33 35 50 71 8 23 34 41 — — 8 25 35 5651 98 8 27 36 94 52 72 8 29 37 62 — — 8 30 38 31 — — 8 31 39 59 — — 9 1740 29 — — 9 21 41 42 53 62 9 27 42 57 54 92 9 31 43 53 — — 10 21 44 87 —— 11 21 45 85 — — 12 21 46 50 55 43 12 27 47 53 56 63 12 31 48 84 — —

Compounds of the formula (I) wherein A¹ is N may also be prepared bycyclising a compound of the formula (X) with a compound of the formula(XI):

wherein R², R⁴, B¹, B², X, X¹, n, a and b are as defined herein.

Representative compounds may be prepared according to Scheme 7 below:

Certain intermediates used in the preparation of compounds of theinvention are novel and form a further feature of the invention.Accordingly, also provided is a compound of the formula (XII) or (XIII),or a pharmaceutically acceptable salt thereof:

wherein A², B¹, B², R⁴, X, X¹, a, b, and n have any of the valuesdefined herein.Examples of compounds of the formulae (XII) and XIII) include a compoundselected from

or a pharmaceutically acceptable salt thereof.

For example a compound selected from:

or a pharmaceutically acceptable salt thereof.

Further Embodiments

Also disclosed are the following numbered clauses as further embodimentsillustrating the invention:

1. A compound of the formula (I), or a pharmaceutically acceptable saltthereof:

A¹ is N or CR¹;A² is N or CR³;and wherein only a single one of A¹ and A² may be N;R¹ is selected from the group consisting of: H, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A1) and —C(O)NR^(A1)R^(B1);R² is selected from the group consisting of: H, CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A2) and —C(O)NR^(A2)R^(B2);R³ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl,—C₁₋₄ alkyl-OR^(A3) and —C(O)NR^(A3)R^(B3);each X is independently H or F, provided at least one X is F;B¹ and B² are independently CH or N;R⁴ is halo;X¹ is O or CH₂;R^(A1), R^(B1), R^(A2), R^(B2), R^(A3) and R^(B3) are each independentlyselected from: H and C₁₋₄ alkyl;a is an integer selected from 0, 1 or 2;b is an integer selected from 0, 1 or 2;a+b is 0, 1, 2 or 3; andn is 0, 1 or 2;with the following provisos:R¹, R² and R³ are not all H;(ii) when A¹ is N, at least one of R² and R³ is C₁₋₄ alkyl or C₁₋₄haloalkyl;(iii) when A² is N, at least one of R¹ and R² is C₁₋₄ alkyl or C₁₋₄haloalkyl; and(iv) when A¹ is CR¹, R¹ is —CH₂OH and B¹ is N, then R² is not H.2. The compound of clause 1, wherein the group —CX₃ is —CF₃.3. The compound of clause 1 or clause 2, wherein B² is CH.4. The compound of clause 1, wherein the compound is of the formula(III), or a pharmaceutically acceptable salt thereof:

5. The compound of any of clauses 1 to 4, wherein n is 0.6. The compound of any of clauses 1 to 5, wherein B¹ is N.7. The compound of any of clauses 1 to 5, wherein B¹ is CH.8. The compound of any of clauses 1 to 7, wherein A¹ is N or CR¹ and R¹is selected from the group consisting of: H, CN, C₁₋₃ alkyl, C₁₋₃fluoroalkyl, alkyl-OH, —C₁₋₃ alkyl-OMe, —C(O)NH₂; —C(O)NHMe and—C(O)N(Me)₂.9. The compound of any of clauses 1 to 8, wherein A¹ is CR¹ and R¹ isCN.10. The compound of any of clauses 1 to 9, wherein R² is selected fromthe group consisting of: H, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, alkyl-OH and—C₁₋₃ alkyl-OMe.11. The compound of any of clauses 1 to 10, wherein A² is N or CR³ andR³ is selected from the group consisting of: H, C₁₋₃ fluoroalkyl and—C₁₋₃ alkyl-OH.12. The compound of any of clauses 1 to 7, wherein the group of theformula:

is selected from the group consisting of:

13. The compound of clause 1 selected from:

14. A pharmaceutical formulation comprising a compound of any of clauses1 to 13 and a pharmaceutically acceptable excipient.15. A compound of any of clauses 1 to 13, for use as a medicament.16. A compound of any of clauses 1 to 13 for use in the treatment of acondition which is modulated by an AMPA receptor.17. A compound of any of clauses 1 to 13, for use in the treatment of adepressive disorder or a mood disorder.18. A compound of any of clauses 1 to 13, for use in the treatment of atreatment-resistant depressive disorder.19. A compound of any of clauses 1 to 13, for use in the treatment ofcognitive dysfunction.20. The compound for the use of clause 19, wherein the cognitivedysfunction is associated with a neurological or neuropsychiatricdisorder.21. A compound of any of clauses 1 to 13 for use in the treatment of acentral nervous system disorder associated with an alteration in one ormore of cognitive function, synaptic plasticity or an imbalance inexcitatory/inhibitory neurotransmission.22. A compound for the use of clause 20 or clause 21, wherein thedisorder is selected from: schizophrenia, bipolar disorder,attention-deficit hyperactivity disorder, a depressive disorder, aneurodegenerative disorder (for example Alzheimer's disease,Huntington's disease or Parkinson's disease), a neurodevelopmentaldisorder, a motor neuron disease (for example amyotrophic lateralsclerosis), ataxia, respiratory depression and a hearing disorder.23. A compound of any of clauses 1 to 13 for use in the treatment ofcognitive dysfunction associated with schizophrenia24. A compound for the use of any of clauses 15 to 23, wherein thecompound is co-administered to a subject with an additional therapeuticagent.25. A compound for the use of clause 24, wherein the additionaltherapeutic agent is selected from an antipsychotic and ananti-depressant.26. A compound selected from:

EXAMPLES

Throughout this specification these abbreviations have the followingmeanings:Ac=acetylAq.=aqueous

(Bpin)₂=Bis(pinacolato)diboron

DCM=dichloromethaneDeoxo-Fluor®=bis(2-methoxyethyl)aminosulfur trifluoride solutionDIBAL-H=diisobutylaluminium hydride

DIPEA=N,N-diisopropylethylamine

DMA=dimethylacetamide

DMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxideEt=ethylEtOAc=ethyl acetateh=hoursHATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphateHEPES=4-(2-Hydroxyethyl)-1-piperazineethanesulponic acidKOAc=potassium acetateMe=methylMeCN=acetonitrilemin=minutesmol=moleMsCl=mesyl chloride

NBS=N-bromosuccinimidePd(dppf)Cl₂=1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

Pd(PPh₃)₂Cl₂=bis(triphenylphosphine)palladium(II) dichloridePhOP(O)Cl₂=phenyl dichlorophosphatepTsOH=para-toluene sulfonic acidR_(t)=retention timeRT=room temperatureSat.=saturated

TEMPO=(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl

TMPMgCl.LiCl=2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithiumchloride complexTHF=tetrahydrofuran

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated.

LCMS data was recorded on a Waters 2695 HPLC using a Waters 2487 UVdetector and a Thermo LCQ ESI-MS. Samples were eluted through aPhenomenex Luna 3μ C18 50 mm×4.6 mm column, using water and acetonitrileacidified by 0.1% formic acid at 1.5 mL/min and detected at 254 nm.

The methods employed were:

4 Minute Method

The gradient employed was:

Time % Water + 0.1% % MeCN + 0.1% (minutes) formic acid formic acid 0.065 35 3.5 10 90 3.9 10 90 4.0 65 35

7 Minute Method

The gradient employed was:

Time % Water + 0.1% % MeCN + 0.1% (minutes) formic acid formic acid 0.070 30 5.0 10 90 6.0 10 90 6.5 70 30 7.0 70 30

10 Minute Method

The gradient employed was:

Time % Water + 0.1% % MeCN + 0.1% (minutes) formic acid formic acid 0.095 5 8.0 5 95 8.5 5 95 9.0 95 5 9.5 95 5

NMR was also used to characterise final compounds. NMR spectra wererecorded at 400, 500 or 600 MHz on a Varian VNMRS 400, 500 or 600 MHzspectrometer (at 30° C.), using residual isotopic solvent (CHCl₃,δ_(H)=7.27 ppm, DMSO δ_(H)=2.50 ppm, MeOH δ_(H)=3.31 ppm) as an internalreference. Chemical shifts are quoted in parts per million (ppm).Coupling constants (J) are recorded in Hertz.

1-[(4-Bromophenyl)methyl]pyrrolidin-2-one (3)

To a solution of pyrrolidin-2-one (1.3 mL, 16.8 mmol) inN,N-dimethylformamide (10 mL) at 0° C. was added sodium hydride (60% inoil) (0.77 g, 19.2 mmol) portionwise and the mixture was left stirringat 0° C. for about 30 min. Then 4-bromobenzyl bromide (1) (4.00 g, 16.0mmol) was added portionwise over 5 min. The reaction mixture was allowedto warm to room temperature and stirred for 16 hours. The reactionmixture was quenched with water, diluted with EtOAc (100 mL), theorganic layer was washed with brine (3×100 mL), dried (MgSO₄) andsolvent evaporated under reduced pressure, the crude material waspurified by column chromatography (50 g, silica) eluting withpetrol:EtOAc (1:1). The desired fractions were concentrated underreduced pressure to afford the title compound as a clear colourless oil(3.74 g, 90%). R_(f) 0.29 (1:3 ethyl acetate:petrol); ¹H NMR (500 MHz,Chloroform-d) δ 7.46 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 4.41 (s,2H), 3.26 (t, J=7.1 Hz, 2H), 2.45 (t, J=8.1 Hz, 2H), 2.00 (p, J=7.6 Hz,2H); LCMS (7 minute method) product at R_(t)=2.83 min and ES⁺ m/z254.28, 256.13 [M+H]⁺ (Br isotope)

1-[[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8)

To flask containing 1-[(4-bromophenyl)methyl]pyrrolidin-2-one (3) (3.74g, 14.7 mmol), bis(pinacolato)diboron (5.61 g, 22.1 mmol), potassiumacetate (4.33 g, 44.2 mmol), and Pd(dppf)Cl₂ (538 mg, 0.74 mmol) wasevacuated and charged with nitrogen 3 times. Dimethyl sulfoxide (40 mL)was added to the solids and the reaction mixture was heated at 90° C.for 4 hours. The reaction mixture was allowed to cool to roomtemperature where it was diluted with EtOAc (100 mL) and extracted withbrine (3×50 mL).

The organic phase was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography (40 g silica, petrol:EtOAc, 100:0 to 50:50). The desiredfractions were concentrated under reduced pressure to afford the titlecompound as a clear pale yellow oil (4.2 g 95%); R_(f) 0.39 (1:1 ethylacetate:petrol); ¹H NMR (500 MHz, Chloroform-d) δ 7.78 (d, J=7.6 Hz,2H), 7.25 (d, J=7.7 Hz, 2H), 4.47 (s, 2H), 3.24 (t, J=7.1 Hz, 2H), 2.45(t, J=8.1 Hz, 2H), 1.99 (p, J=7.6 Hz, 2H), 1.35 (s, 12H); LCMS (7 minutemethod) product at R_(t)=3.52 min and ES⁺ m/z 302.11 [M+H]⁺

4-[(4-Bromophenyl)methyl]morpholin-3-one (4)

To a solution of morpholin-3-one (2.22 g, 22.0 mmol) inN,N-dimethylformamide (25 mL) at 0° C. was added sodium hydride (60% inoil) (967 mg, 24.2 mmol) portionwise. The reaction mixture was allowedto stir at 0° C. for 30 minutes before the portionwise addition of4-bromobenzyl bromide (1) (5.00 g, 20.0 mmol). The reaction mixture wasallowed to warm to room temperature where it was stirred for 4 hours.The reaction was quenched with deionised water (2 mL), diluted withEtOAc (100 mL) and washed with brine (3×100 mL). The organic phase wasdried over MgSO₄, filtered and concentrated under reduced pressure toafford the title compound as a colourless oil (5.5 g, 97%); ¹H NMR (500MHz, Chloroform-d) δ 7.46 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H),4.57 (s, 2H), 4.24 (s, 2H), 3.90-3.79 (m, 2H), 3.32-3.19 (m, 2H); LCMS(4 minute method) product at R_(t)=1.80 min and ES⁺ m/z 269.96, 271.92[M+H]⁺ (Br isotope)

4-[[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one(9)

To flask containing 4-[(4-bromophenyl)methyl]morpholin-3-one (4) (5.5 g,20.3 mmol), bis(pinacolato)diboron (7.76 g, 30.5 mmol), potassiumacetate (5.99 g, 61.1 mmol), and Pd(dppf)Cl₂ (744 mg, 1.02 mmol) wasevacuated and charged with nitrogen 3 times. Dimethyl sulfoxide (55 mL)was added to the solids and the reaction mixture was heated at 90° C.for 4 hours. The reaction mixture was allowed to cool to roomtemperature where it was diluted with EtOAc (250 mL) and extracted withbrine (3×100 mL).

The organic phase was dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography (100 g silica, petrol:EtOAc, 100:0 to 40:60, NOTE: veryweak UV signal). The desired fractions were concentrated under reducedpressure to afford the title compound as a white solid (5.3 g, 78%).R_(t) 0.39 (1:1 ethyl acetate:petrol); ¹H NMR (500 MHz, Chloroform-d) δ7.78 (d, J=7.7 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 4.63 (s, 2H), 4.25 (s,2H), 3.90-3.75 (m, 2H), 3.29-3.13 (m, 2H), 1.33 (s, 12H); LCMS (4 minutemethod) product at R_(t)=2.41 min and ES⁺ m/z 318.08 [M+H]⁺

4-[(4-Bromophenyl)methyl]-1,4-oxazepan-3-one (5)

To a solution of 1,4-oxazepan-3-one (400 mg, 3.47 mmol) inN,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% inoil) (181 mg, 4.52 mmol) portionwise and the mixture was left stirringat 0° C. for 30 minutes. 4-Bromobenzyl bromide (1) (912 mg, 3.65 mmol)was then added portionwise and the reaction mixture allowed to warm toroom temperature where it was stirred for 16 hours. The reaction mixturewas quenched with water (2 mL) and concentrated to dryness. The residuewas taken up in EtOAc (50 mL) and the organic phase was washed withwater (2×50 mL) then saturated brine solution (1×50 mL). The organicphase was dried (MgSO₄), filtered and concentrated to dryness underreduced pressure to afford the title compound as a white solid (1.07 g,99%) as a white solid; ¹H NMR (500 MHz, Chloroform-d) δ 7.46 (d, J=8.4Hz, 2H), 7.16 (d, J=8.2 Hz, 2H), 4.56 (s, 2H), 4.31 (s, 2H), 3.81 (t,J=6.0 Hz, 2H), 3.46-3.37 (m, 2H), 1.91-1.80 (m, 2H); LCMS (4 minutemethod) product at R_(t)=0.53 min and ES⁺ m/z 284.04, 286.01 [M+H]⁺ (Brisotope)

4-[[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1,4-oxazepan-3-one(10)

To bis(pinacolato)diboron (1.43 g, 5.65 mmol), Pd(dppf)Cl₂ (138 mg, 0.19mmol) and 4-[(4-bromophenyl)methyl]-1,4-oxazepan-3-one (5) (1.07 g, 3.77mmol) under nitrogen was added potassium acetate (1.11 g, 11.3 mmol),followed by dry dimethyl sulfoxide (10 mL) and the reaction mixture washeated at 90° C. for 4 hours. The reaction mixture was cooled to roomtemperature and diluted with EtOAc (100 mL). The organic phase waswashed with brine (3×50 mL), dried (MgSO₄), filtered and evaporatedunder reduced pressure to give the crude product which was purified byflash column chromatography eluting petrol:EtOAc (90:10 to 50:50). Thedesired fractions were combined and concentrated to dryness underreduced pressure to afford the title compound as a white solid (1.04 g,84%); ¹H NMR (500 MHz, Chloroform-d) δ 7.78 (d, J=8.0 Hz, 2H), 7.28 (d,J=8.1 Hz, 2H), 4.63 (s, 2H), 4.32 (s, 2H), 3.80 (t, J=5.9 Hz, 2H),3.43-3.36 (m, 2H), 1.85-1.76 (m, 2H), 1.35 (s, 12H); LCMS (4 minutemethod) product at R_(t)=2.20 min and ES⁺ m/z 332.14 [M+H]⁺

4-[(4-Bromophenyl)methyl]-1,4-oxazepan-5-one (6)

To a solution of 1,4-oxazepan-5-one (400 mg, 3.47 mmol) inN,N-dimethylformamide (5 mL) at 0° C. was added sodium hydride (60% inoil) (181 mg, 4.52 mmol) portionwise and the mixture was left stirringat 0° C. for 30 minutes. 4-Bromobenzyl bromide (1) (912 mg, 3.65 mmol)was then added portionwise and the reaction mixture allowed to warm toroom temperature where it was stirred for 16 hours. The reaction mixturewas quenched with water (2 mL) and concentrated to dryness. The residuewas taken up in EtOAc (50 mL) and this was washed with water (2×50 mL)then saturated brine solution (1×50 mL). The organic phase was dried(MgSO₄), filtered and concentrated to dryness under reduced pressure toafford the title compound as a white oily solid (1.12 g, 96%); ¹H NMR(500 MHz, Chloroform-d) δ 7.46 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz,2H), 4.55 (s, 2H), 3.84-3.75 (m, 2H), 3.63-3.54 (m, 2H), 3.44-3.37 (m,2H), 2.86-2.79 (m, 2H); LCMS (4 minute method) product at R_(t)=1.50 minand ES⁺ m/z 284.04, 286.01 [M+H]⁺ (Br isotope)

4-[[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1,4-oxazepan-5-one(11)

To bis(pinacolato)diboron (1.28 g, 5.03 mmol), Pd(dppf)Cl₂ (123 mg, 0.17mmol) and 4-[(4-bromophenyl)methyl]-1,4-oxazepan-5-one (6) (1.12 g, 3.35mmol) under nitrogen was added potassium acetate (0.99 g, 10.05 mmol),followed by dry dimethyl sulfoxide (10 mL) and the reaction mixture washeated at 90° C. for 4 hours. The reaction mixture was cooled to roomtemperature and diluted with EtOAc (100 mL). This was washed with brine(3×50 mL), dried (MgSO₄), filtered and evaporated under reduced pressureto give the crude product which was purified by flash columnchromatography eluting petrol:EtOAc (90:10 to 50:50). The desiredfractions were concentrated under reduced pressure to afford the titlecompound as a white solid (694 mg, 63%); ¹H NMR (500 MHz, Chloroform-d)δ 7.77 (d, J=7.4 Hz, 2H), 7.30-7.24 (m, 2H), 4.63 (s, 2H), 3.85-3.76 (m,2H), 3.58-3.51 (m, 2H), 3.44-3.35 (m, 2H), 2.88-2.80 (m, 2H), 1.35 (s,12H); LCMS (4 minute method) product at R_(t)=2.11 min and ES⁺ m/z332.14 [M+H]⁺

1-[(5-Bromo-2-pyridyl)methyl]pyrrolidin-2-one (7)

To a mixture of (5-bromo-2-pyridyl)methanol (2) (5.0 g, 26.6 mmol) andN,N-diisopropylethylamine (5.56 mL, 31.9 mmol) in DCM (50 mL) at 0° C.was added methanesulfonyl chloride (2.37 mL, 30.6 mmol) dropwise. Thereaction mixture was allowed to warm to room temperature slowly andafter stirring for 16 hours was concentrated under reduced pressure toafford a yellow oil. The yellow oil was dissolved in EtOAc (30 mL),washed with sat. aq. NaHCO₃, dried over MgSO₄ and concentrated underreduced pressure to afford a yellow oil. To a suspension of sodiumhydride (60% in oil) (1.38 g, 34.6 mmol) in tetrahydrofuran (50 mL)cooled at 0° C. was added pyrrolidin-2-one (2.63 mL, 34.6 mmol) slowly(gas evolution). The reaction mixture was stirred for a further 30minutes at this temperature. The crude mesylate in tetrahydrofuran (50mL) was added dropwise to the reaction mixture maintaining thetemperature below 25° C. The resulting reaction mixture was stirred for72 hours at room temperature. The solvent was removed under reducedpressure and the residual material diluted with ethyl acetate (50 mL).The organic layer was washed with sat. aq. NaHCO₃ (30 mL) and brine (30mL), dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (100 g silica,petrol:EtOAc, 100:0 to 0:100). The desired fractions were concentratedunder reduced pressure to afford the title compound as a yellow oil (5.4g, 76%); R_(t) 0.19 (100% ethyl acetate); ¹H NMR (500 MHz, Chloroform-d)δ 8.60 (d, J=2.3 Hz, 1H), 7.79 (dd, J=8.3, 2.2 Hz, 1H), 7.19 (d, J=8.3Hz, 1H), 4.55 (s, 2H), 3.41 (t, J=7.1 Hz, 2H), 2.45 (t, J=8.1 Hz, 2H),2.05 (p, J=7.6 Hz, 2H); LCMS (4 minute method) product at R_(t)=0.63 minand ES⁺ m/z 255.11, 257.13 [M+H]⁺ (Br isotope)

1-[[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]methyl]pyrrolidin-2-one(12)

To 1-[(5-bromo-2-pyridyl)methyl]pyrrolidin-2-one (7) (510 mg, 2.00mmol), bis(pinacolato)diboron (761 mg, 3.00 mmol) and potassium acetate(588 mg, 6.00 mmol) under nitrogen was added Pd(dppf)Cl₂ (73 mg, 0.10mmol), followed by dry 1,4-dioxane (14 mL) and the reaction mixture washeated at 80° C. for 5 hours. The reaction mixture was cooled to roomtemperature, diluted with EtOAc (100 mL) and the organic phase waswashed with brine (3×50 mL), dried (MgSO₄), filtered and evaporatedunder reduced pressure to give the crude product as a runny brown oil.The crude material was purified by flash silica column chromatographyeluting petrol:EtOAc (50:50 to 0:100), then 100% EtOAc to 10% MeOH inEtOAc. The desired fractions were concentrated under reduced pressure toafford the title compound as a light brown oil (138 mg, 23%); ¹H NMR(500 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.26 (d,J=7.8 Hz, 1H), 4.62 (s, 2H), 3.38 (t, J=7.1 Hz, 2H), 2.45 (t, J=8.1 Hz,2H), 2.07-1.98 (m, 2H), 1.35 (s, 12H); LCMS (4 minute method) product atR_(t)=0.40 min and ES⁺ m/z 302.96 [M+H]⁺

Ethyl 2-hydroxy-6-(trifluoromethyl)-3,4-dihydropyridine-5-carboxylate(14)

A mixture of ethyl 4,4,4-trifluoroacetoacetate (13) (14.8 mL, 101 mmol),acrylamide (4.5 g, 63.3 mmol) and p-toluenesulfonic acid monohydrate(0.16 g, 0.82 mmol) in toluene (60 mL) was refluxed for about 48 hourswith azeotropic removal of water with a Dean-Stark apparatus. Thereaction mixture was then concentrated to a small volume, by slowdistillation of toluene at atmospheric pressure. Toluene (60 mL) wasadded and again the reaction mixture was concentrated, through slowdistillation of toluene. After repeating this operation three times, thereaction mixture was concentrated under reduced pressure to give ayellow solid. The crude material was dissolved in EtOAc and theinsoluble material was filtered off and the filtrate was evaporatedunder reduced pressure to afford a yellow solid (12 g). The crudematerial was purified twice by column chromatography (SiO₂, 25 g)gradient eluent 100% DCM to 9:1 DCM:MeOH. The desired fractions wereconcentrated under reduced pressure to afford the title compound as alight yellow solid (4.6 g. 31%); ¹H NMR (500 MHz, Chloroform-d) δ 4.28(q, J=7.1 Hz, 2H), 2.85-2.72 (m, 2H), 2.65-2.53 (m, 2H), 1.33 (t, J=7.2Hz, 3H); LCMS (4 minute method) product at R_(t)=1.17 min and ES⁺ m/z238.07 [M+H]⁺

Ethyl 6-hydroxy-2-(trifluoromethyl)pyridine-3-carboxylate (15)

A solution of ethyl2-hydroxy-6-(trifluoromethyl)-3,4-dihydropyridine-5-carboxylate (14)(2.8 g, 11.8 mmol) and N-bromosuccinimide (2.1 g, 11.8 mmol) in carbontetrachloride (25 mL) was heated at reflux overnight. The resultingprecipitate was filtered off and the filtrate was concentrated underreduced pressure to afford a yellow solid that was purified by flashchromatography (silica gel 24 g, eluent gradient: from petrol:EtOAc 9:1to 1:1. The desired fractions were concentrated under reduced pressureand repurified by column chromatography (SiO₂, 10 g, eluent petrol:EtOAC9:1 to 1:1). The desired fractions were concentrated under reducedpressure to afford the title compound as a white solid (890 mg, 32%); ¹HNMR (500 MHz, Chloroform-d) δ 8.01 (d, J=9.2 Hz, 1H), 6.87 (d, J=9.2 Hz,1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H); LCMS (4 minutemethod) product at R_(t)=0.44 min and ES⁺ m/z 236.09 [M+H]⁺

Ethyl 6-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (16)

A mixture of ethyl 6-hydroxy-2-(trifluoromethyl)pyridine-3-carboxylate(15) (890 mg, 3.78 mmol) and phenyl dichlorophosphate (0.85 mL, 5.68mmol) was heated under microwave irradiation for 30 min at 170° C. Thereaction mixture was poured into ice, stirred for 20 min and dilutedwith ethyl acetate (50 mL). The pH was adjusted to 10, by addition of asat. aq. solution of sodium bicarbonate (50 mL) and then the organiclayer was separated, washed with water, dried over Na₂SO₄ andconcentrated under reduced pressure to give a brown oil which waspurified by column chromatography (SiO₂, 12 g, gradient elution 100%petrol to 50% EtOAc in petrol). The desired fractions were concentratedunder reduced pressure to afford the title compound as a clear oil (650mg, 68%; ¹H NMR (500 MHz, Chloroform-d) δ 8.09 (d, J=8.3 Hz, 1H), 7.60(d, J=8.2 Hz, 1H), 4.44 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H); LCMS(4 minute method) product at R_(t)=2.02 min and ES⁺ m/z 254.04, 256.02[M+H]⁺ (Cl isotope)

[6-Chloro-2-(trifluoromethyl)-3-pyridyl]methanol (17)

To a solution of ethyl6-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (16) (650 mg, 2.56mmol) in DCM (50 mL) at 0° C. was added diisobutylaluminum hydride (1 Msolution in toluene) (7.69 mL, 7.69 mmol) and the mixture was slowlyallowed to warm to room temperature and stirred overnight.Diisobutylaluminum hydride (1 M solution in toluene) (7.69 mL, 7.69mmol) was added to the reaction mixture at 0° C. and allowed to warm upto room temperature and was stirred for 72 hours. The reaction mixturewas quenched with sat. aq. Rochelle's salt and stirred for 30 min beforeconcentrating down the solution. The product was then extracted intoEtOAc (3×30 mL) the combined organic layers were washed with brine (50mL), dried (MgSO₄) and solvent evaporated to leave a clear oil. Thecrude was purified by column chromatography (SiO₂, 10 g, gradientelution 10% EtOAc in petrol to 50% EtOAc in petrol). The desiredfractions were concentrated to dryness under reduced pressure to affordthe title compound as a light yellow oil (350 mg, 64%); ¹H NMR (500 MHz,Chloroform-d) δ 8.14 (d, J=8.3 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H), 4.93 (s,2H); LCMS (4 minute method) product at R_(t)=1.39 min and ES⁺ m/z212.22, 214.22 [M+H]⁺ (Cl isotope).

Ethyl 4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate (19)

To a solution of ethyl malonate monoamide (18) (2.34 g, 17.9 mmol) and(E)-1,1,1-trifluoro-4-methoxy-pent-3-en-2-one (3.00 g, 17.9 mmol) inethanol (20 mL) was added sodium ethoxide (21 wt % solution in ethanol)(6.3 mL, 92.7 mmol) and the mixture was heated to 85° C. overnight.Aqueous 2 M HCl (15 mL) was added to the reaction mixture, the solventconcentrated down under reduced pressure and the product extracted intoEtOAc (2×30 mL). The combined organic layers were washed with brine (25mL), dried (MgSO₄), filtered and solvent evaporated under reducedpressure to afford the title compound as an orange oil (3.6 g, 73%); ¹HNMR (500 MHz, Chloroform-d) δ 7.07 (s, 1H), 4.51 (q, J=7.1 Hz, 2H), 2.63(s, 3H), 1.46 (t, J=7.1 Hz, 3H); LCMS (4 minute method) product atR_(t)=2.20 min and ES⁺ m/z 249.97 [M+H]⁺

Ethyl 2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (20)

A mixture of ethyl4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate (19) (1.56g, 6.26 mmol) and phenyl dichlorophosphate (3.27 mL, 21.9 mmol) washeated under microwave irradiation for 30 min at 165° C. The reactionmixture was poured into ice, stirred for 20 min and diluted with ethylacetate (50 mL). The pH was adjusted to 10, by addition of sat. aq.NaHCO₃ (50 mL) and then the organic layer was separated, washed withwater, dried over Na₂SO₄ and concentrated under reduced pressure to givea brown oil which was purified by flash chromatography (silica gel 25 g,eluent gradient: 100% petrol to 50% EtOAc in petrol). The desiredfractions were concentrated under reduced pressure to afford the titlecompound as a yellow oil (615 mg, 36%); ¹H NMR (500 MHz, Chloroform-d) δ7.49 (s, 1H), 4.48 (q, J=7.2 Hz, 2H), 2.45 (s, 3H), 1.43 (t, J=7.2 Hz,3H); LCMS (4 minute method) product at R_(t)=3.03 min and ES⁺ m/z 268.09[M+H]⁺

[2-Chloro-4-methyl-6-(trifluoromethyl)-3-pyridyl]methanol (21)

To a solution of ethyl2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (20) (800mg, 2.99 mmol) in DCM (25 mL) at 0° C. was added diisobutylaluminumhydride (1 M solution in toluene) (8.97 mL, 8.97 mmol) and the mixturewas slowly allowed to stirred at room temperature. After about an hourmore diisobutylaluminum hydride (1 M solution in toluene) (8.97 mL, 8.97mmol) was added and the reaction was then left to stir at roomtemperature overnight. The reaction mixture was quenched with sat. aq.Rochelle's salt and stirred for 30 min. The product was then extractedinto DCM (3×35 mL) and the combined organic layers were washed withbrine (50 mL), dried (MgSO₄) and solvent evaporated under reducedpressure to afford the title compound as a white solid (525 mg, 78%); ¹HNMR (500 MHz, Chloroform-d) δ 7.47 (s, 1H), 4.90 (s, 2H), 2.58 (s, 3H);LCMS (4 minute method) product at R_(t)=1.60 min and ES⁺ m/z the desiredmas ion was not observed.

2-Chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic Acid (22)

To a solution of ethyl2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (20) (488mg, 1.82 mmol) in tetrahydrofuran (2 mL) and ethanol (0.50 mL) was addedsodium hydroxide (1.0 M in H₂O) (3.65 mL, 3.65 mmol). The reactionmixture was stirred at room temperature overnight and then heated to 50°C. for a further 24 hours. The solvent was concentrated under reducedpressure, water was added (10 mL) and solution washed with EtOAc (2×10mL). The aqueous layer was acidified with aqueous HCl (1.0 M) untilneutral pH and the product was extracted into EtOAc (2×10 mL). Thecombined organic extracts were washed with brine, and dried over MgSO₄,filtered, and concentrated under reduced pressure to afford the titlecompound as a light yellow solid (370 mg, 80%); ¹H NMR (500 MHz,DMSO-d₆) δ 7.97 (s, 1H), 2.43 (s, 3H); LCMS (4 minute method) product atR_(t)=1.55 min and ES⁺ m/z the desired mass ion was not observed.

2-Chloro-N,4-dimethyl-6-(trifluoromethyl)pyridine-3-carboxamide (23)

To a solution of HATU (523 mg, 1.38 mmol) in N,N-dimethylformamide (25mL) were added a solution of methyl amine (2.0 M in THF) (1.88 mL, 3.76mmol), N,N-diisopropylethylamine (0.44 mL, 2.5 mmol) and2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (22)(300 mg, 1.25 mmol) at room temperature.

The resulting mixture was stirred at room temperature for 72 hours. Thesolvent was removed under reduced pressure and the residual materialdiluted with ethyl acetate (30 mL). The organic layer was washed withbrine (30 mL), sat aq. NaHCO₃ (30 mL), dried over MgSO₄ and concentratedunder reduced pressure to give a light orange oil. The crude wasdissolved in DCM (20 mL) and washed with brine (15 mL). The organiclayer was dried (MgSO₄) and the solvent was concentrated under reducedpressure to leave an orange solid. The crude material was purified bycolumn chromatography (SiO₂, 10 g, gradient elution 10% EtOAc in petrolto 50% EtOAc in petrol). The desired fractions were combined andconcentrated under reduced pressure to afford the title compound a whitesolid (84 mg, 26%); ¹H NMR (500 MHz, Chloroform-d) δ 7.48 (s, 1H), 5.89(s, 1H), 3.06 (d, J=4.9 Hz, 3H), 2.46 (s, 3H); LCMS (4 minute method)product at R_(t)=0.79 min and ES⁺ m/z 253.09 [M+H]⁺

[4-Chloro-2-(trifluoromethyl)pyrimidin-5-yl]methanol (25)

To a solution ofethyl-4-chloro-2-(trifluoromethyl)pyrimidin-5-carboxylate (24) (510 mg,2.0 mmol) in DCM (10 mL) at 0° C. was added diisobutylaluminum hydride(1 M solution in toluene) (6.0 mL, 6.0 mmol). The mixture was slowlyallowed to warm to room temperature and was stirred overnight. Thereaction mixture was quenched with sat. aq. Rochelle's salt and stirredfor 30 min before concentrating down the solution. The product was thenextracted into EtOAc (3×30 mL) and the combined organic layers werewashed with brine (50 mL), dried (MgSO₄) and solvent evaporated to leavea clear oil. The crude was purified by column chromatography (SiO₂, 10g, gradient elution 10% EtOAc in petrol to 50% EtOAc in petrol). Thedesired fractions were concentrated under reduced pressure to afford thetitle compound as a yellow oil (96 mg, 23%); ¹H NMR (500 MHz,Chloroform-d) δ 9.01 (s, 1H), 4.92 (s, 2H); LCMS (4 minute method)product at R_(t)=0.44 min and ES⁺ m/z the desired mass ion was notobserved.

[2-Chloro-6-(trifluoromethyl)-3-pyridyl]methanol (27)

To a solution of 2-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid(26) (1.07 g, 4.74 mmol) in tetrahydrofuran (15 mL) at 0° C. was addedborane (1.0 M in tetrahydrofuran) (9.49 mL, 9.49 mmol) dropwise and themixture was slowly allowed to warm up to room temperature and stirredovernight. Borane (1.0 M in tetrahydrofuran) (3.0 mL, 3.0 mmol) wasadded to the reaction mixture and stirred further for 16 hours. Thereaction mixture was quenched with methanol (0.2 mL) and stirred for 30min before concentrating down the solution. The residue was then dilutedwith water (30 mL) and extracted into EtOAc (3×30 mL). The combinedorganic layers were washed with brine (50 mL), dried (MgSO₄) and solventevaporated to leave a clear oil. The crude material was purified bycolumn chromatography (SiO₂, 25 g, gradient elution 10% EtOAc in petrolto 50% EtOAc in petrol). The desired fractions were concentrated todryness under reduced pressure to afford the title compound as acolourless oil (1.02 g, 100%); ¹H NMR (500 MHz, Chloroform-d) δ 8.11 (d,J=7.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 4.86 (s, 2H); LCMS (4 minutemethod) product at R_(t)=0.62 min and ES⁺ m/z the desired mas ion wasnot observed.

2-Chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carbonitrile (29)

A mixture of 2-hydroxy-4-methyl-6-(trifluoromethyl)nicotinonitrile (28)(200 mg, 0.99 mmol) and phenyl dichlorophosphate (0.52 mL, 3.46 mmol)was heated under microwave irradiation for 30 min at 170° C. Thereaction mixture was poured into ice, stirred for 20 min and dilutedwith ethyl acetate (20 mL). The pH was adjusted to 10, by addition ofsat. aq. NaHCO₃. The organic layer was separated, washed with brine (20mL), dried over MgSO₄ and concentrated under reduced pressure to affordthe title compound as a clear oil (177 mg, 77%); ¹H NMR (500 MHz,Chloroform-d) δ 7.60 (s, 1H), 2.71 (s, 3H); LCMS (4 minute method)product at R_(t)=0.60 min and ES⁺ m/z the desired mas ion was notobserved.

Example 1:1-[[4-[5-(Hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(32)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (334 mg, 1.11 mmol), bis(triphenylphosphine)palladium(II) dichloride(38 mg, 0.055 mmol), [6-chloro-2-(trifluoromethyl)-3-pyridyl]methanol(17) (235 mg, 1.11 mmol) and sodium carbonate (353 mg, 3.33 mmol) inacetonitrile (15 mL) and water (1 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor at 140° C. for 20 min. Thereaction was diluted with water (30 mL) and extracted into EtOAc (2×30mL). The combined organic extracts were dried (MgSO₄), filtered andevaporated under reduced pressure to give a beige solid (400 mg) whichwas purified by column chromatography (12 g, silica) gradient elution80% EtOAc in petrol to 100% EtOAc. The desired fractions wereconcentrated to dryness under reduced pressure to afford the titlecompound as a white solid (210 mg, 54%); ¹H NMR (500 MHz, Chloroform-d)δ 8.17 (d, J=8.2 Hz, 1H), 8.03 (d, J=8.1 Hz, 2H), 7.93 (d, J=8.2 Hz,1H), 7.36 (d, J=8.0 Hz, 2H), 4.97 (s, 2H), 4.52 (s, 2H), 3.29 (t, J=7.0Hz, 2H), 2.47 (t, J=8.1 Hz, 2H), 2.01 (p, J=7.6 Hz, 2H); LCMS (4 minutemethod) product at R_(t)=1.67 min and ES⁺ m/z 351.17 [M+H]⁺

Example 2:1-[[4-[3-(Hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(33)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (200 mg, 0.66 mmol), bis(triphenylphosphine)palladium(II) dichloride(23 mg, 0.03 mmol),[2-chloro-4-methyl-6-(trifluoromethyl)-3-pyridyl]methanol (21) (149 mg,0.66 mmol) and sodium carbonate (211 mg, 1.99 mmol) in acetonitrile (2mL) and water (0.50 mL) was degassed under a flow of nitrogen and heatedin a microwave reactor at 140° C. for 15 min. The reaction was dilutedwith water (10 mL) and extracted into EtOAc (2×20 mL). The combinedorganics were dried (MgSO₄), filtered and evaporated under reducedpressure to give a crude mixture which was purified by columnchromatography (SiO₂, 4 g, gradient elution: 50% EtOAc in petrol to 100%EtOAc). The desired fractions were combined and concentrated to drynessunder reduced pressure to afford the title compound as a white solid (85mg, 35%); ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J=8.2 Hz, 2H), 7.52(s, 1H), 7.34 (d, J=8.1 Hz, 2H), 4.71 (s, 2H), 4.51 (s, 2H), 3.31 (t,J=7.1 Hz, 2H), 2.63 (s, 3H), 2.45 (t, J=8.1 Hz, 2H), 2.09-1.94 (m, 2H);LCMS (4 minute method) product at R_(t)=1.79 min and ES⁺ m/z 365.10[M+H]⁺

Example 3:N,4-Dimethyl-2-[4-[(2-oxopyrrolidin-1-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide(34)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (90 mg, 0.30 mmol), bis(triphenylphosphine)palladium(II) dichloride(10 mg, 0.010 mmol),2-chloro-N,4-dimethyl-6-(trifluoromethyl)pyridine-3-carboxamide (23) (75mg, 0.30 mmol) and sodium carbonate (95 mg, 0.90 mmol) in acetonitrile(8 mL) and water (2 mL) was degassed under a flow of nitrogen and heatedin a microwave reactor at 145° C. for 20 min. The reaction was dilutedwith water (15 mL) and extracted into EtOAc (2×20 mL). The combinedorganic phases were dried (MgSO₄), filtered and concentrated underreduced pressure to give a crude mixture which was purified by columnchromatography (10 g, silica) eluting with 10% EtOAc in petrol to 100%EtOAc. The desired fractions were combined and concentrated underreduced pressure to afford the title compound as a light yellow oil (51mg, 41%); ¹H NMR (500 MHz, Chloroform-d) δ 7.74 (d, J=8.2 Hz, 2H), 7.52(s, 1H), 7.31 (d, J=8.0 Hz, 2H), 5.46 (q, J=5.0 Hz, 1H), 4.50 (s, 2H),3.28 (t, J=7.0 Hz, 2H), 2.77 (d, J=4.9 Hz, 3H), 2.51 (s, 3H), 2.45 (t,J=8.1 Hz, 2H), 2.04-1.98 (m, 2H); LCMS (4 minute method) product atR_(t)=1.79 min and ES⁺ m/z 392.08 [M+H]⁺

Example 4:1-[[4-[3-(Hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(36)

Split across two microwave vials was a mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (245 mg, 0.81 mmol), bis(triphenylphosphine)palladium(II) dichloride(28.5 mg, 0.041 mmol), [2-chloro-6-(trifluoromethyl)-3-pyridyl]methanol(27) (172 mg, 0.81 mmol) and sodium carbonate (258 mg, 2.44 mmol) inacetonitrile (2 mL) and water (0.5 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor at 140° C. for 15 min. Thereaction mixtures were combined, diluted with water (30 mL) andextracted into EtOAc (2×30 mL). The combined organic layers were dried(MgSO₄), filtered and evaporated under reduced pressure to give a crudemixture which was purified by column chromatography (10 g, silica)eluting with EtOAc:petrol 1:1 to 100% EtOAc. The desired fractions wereconcentrated to dryness under reduced pressure to afford the titlecompound as a colourless oil (268 mg, 94%); ¹H NMR (500 MHz,Chloroform-d) δ 8.16 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.53 (d,J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 4.77 (s, 2H), 4.50 (s, 2H), 3.30(t, J=7.1 Hz, 2H), 2.46 (t, J=8.1 Hz, 2H), 2.06-1.99 (m, 2H); LCMS (4minute method) product at R_(t)=1.55 min and ES⁺ m/z 351.11 [M+H]⁺

Example 5:4-Methyl-2-[4-[(2-oxopyrrolidin-1-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-3-carbonitrile(37)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (165 mg, 0.55 mmol), bis(triphenylphosphine)palladium(II) dichloride(19.2 mg, 0.03 mmol),2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carbonitrile (29) (120mg, 0.55 mmol) and sodium carbonate (174 mg, 1.64 mmol) in acetonitrile(8 mL) and water (2 mL) was degassed under a flow of nitrogen and heatedin a microwave reactor at 140° C. for 15 min. The reaction was dilutedwith water (15 mL) and extracted into EtOAc (2×20 mL). The organics weredried (MgSO₄), filtered and evaporated under reduced pressure to give acrude mixture which was purified by column chromatography (10 g, silica)eluting with 10% EtOAc in petrol to 100% EtOAc. The desired fractionswere combined and concentrated to dryness under reduced pressure toafford the title compound as a white solid (125 mg, 62%); ¹H NMR (500MHz, Chloroform-d) δ 7.93 (d, J=8.2 Hz, 2H), 7.62 (s, 1H), 7.42 (d,J=8.2 Hz, 2H), 4.55 (s, 2H), 3.32 (t, J=7.0 Hz, 2H), 2.75 (s, 3H), 2.48(t, J=8.1 Hz, 2H), 2.10-1.96 (m, 2H); LCMS (4 minute method) product atR_(t)=2.33 min and ES⁺ m/z 360.10 [M+H]⁺

Example 6:1-[[4-[5,6-Dimethyl-2-(trifluoromethyl)pyrimidin-4-yl]phenyl]methyl]pyrrolidin-2-one(38)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (100 mg, 0.33 mmol), bis(triphenylphosphine)palladium(II) dichloride(11.6 mg, 0.020 mmol),4-chloro-5,6-dimethyl-2-(trifluoromethyl)pyrimidine (30) (70 mg, 0.33mmol) and sodium carbonate (105 mg, 1.00 mmol) in acetonitrile (2 mL)and water (0.5 mL) was degassed under a flow of nitrogen and heated in amicrowave reactor at 140° C. for 15 min. The reaction was diluted withwater (30 mL), then extracted into EtOAc (2×30 mL). The combined organiclayers were dried (MgSO₄), filtered and evaporated under reducedpressure to give a crude mixture which was purified twice by columnchromatography (10 g, silica) eluting with EtOAc:petrol 1:1 to 100%EtOAc. The desired fractions were concentrated under reduced pressure toafford a colourless oil (56 mg). This oil was recrystallised fromEt₂O/petrol to afford the title compound as a white solid (36 mg, 31%);¹H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J=8.0 Hz, 2H), 7.38 (d, J=7.9Hz, 2H), 4.53 (s, 2H), 3.32 (t, J=7.1 Hz, 2H), 2.67 (s, 3H), 2.47 (t,J=8.1 Hz, 2H), 2.38 (s, 3H), 2.04 (p, J=7.8 Hz, 2H); LCMS (4 minutemethod) product at R_(t)=2.29 min and ES⁺ m/z 350.14 [M+H]⁺

Example 7:2-[4-[(2-Oxopyrrolidin-1-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-3-carbonitrile(39)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (110 mg, 0.37 mmol), bis(triphenylphosphine)palladium(II) dichloride(13 mg, 0.020 mmol), 2-chloro-6-trifluoromethylnicotinonitrile (31) (75mg, 0.37 mmol) and sodium carbonate (116 mg, 1.10 mmol) in acetonitrile(2 mL) and water (0.5 mL) was degassed under a flow of nitrogen andheated in a microwave reactor at 145° C. for 30 min. The reaction wasdiluted with water (10 mL) and extracted into EtOAc (2×20 mL). Thecombined organic layers were dried (MgSO₄), filtered and evaporatedunder reduced pressure to give a crude mixture which was purified bycolumn chromatography (4 g, silica) eluting with 50% EtOAc in petrol to100% EtOAc. The desired fractions were combined and concentrated todryness under reduced pressure to afford the title compound as a clearoil (75 mg, 59%); ¹H NMR (500 MHz, Chloroform-d) δ 8.27 (d, J=8.1 Hz,1H), 7.99 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.1 Hz, 1H), 7.43 (d, J=8.5 Hz,2H), 4.55 (s, 2H), 3.32 (t, J=7.0 Hz, 2H), 2.47 (t, J=8.1 Hz, 2H),2.10-2.00 (m, 2H); LCMS (4 minute method) product at R_(t)=2.17 min andES⁺ m/z 346.09 [M+H]⁺

Example 8:4-[[4-[5-(Hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(40)

A mixture of4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one(9) (80 mg, 0.25 mmol), [6-chloro-2-(trifluoromethyl)-3-pyridyl]methanol(17) (59 mg, 0.28 mmol), sodium carbonate (80 mg, 0.76 mmol) andbis(triphenylphosphine)palladium(II) dichloride (8.9 mg, 0.010 mmol) inacetonitrile (4 mL) and water (1 mL) was heated in a microwave reactorat 140° C. for 15 min. The reaction was diluted with water (10 mL), theorganic solvent was evaporated and the product was extracted into EtOAc(2×25 mL). The combined organic layers were washed with brine, (20 mL),dried (MgSO₄), filtered and evaporated under reduced pressure to give acrude residue which was purified twice by column chromatography (ISCOCombiflash, 4 g silica) eluting with EtOAc:petrol (50:50 to 100:0). Thedesired fractions were combined and concentrated to dryness underreduced pressure to afford the title compound as a white solid (27 mg,29%); ¹H NMR (500 MHz, Chloroform-d) δ 8.18 (d, J=8.1 Hz, 1H), 8.04 (d,J=7.8 Hz, 2H), 7.92 (d, J=8.3 Hz, 1H), 7.39 (d, J=7.8 Hz, 2H), 4.97 (s,2H), 4.69 (s, 2H), 4.28 (s, 2H), 3.89-3.83 (m, 2H), 3.31 (t, J=5.0 Hz,2H); LCMS (4 minute method) product at R_(t)=1.49 min and ES⁺ m/z 367.22[M+H]⁺

Example 9:4-[[4-[3-(Hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(41)

A mixture of4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one(9) (150 mg, 0.47 mmol), bis(triphenylphosphine)palladium(II) dichloride(16 mg, 0.02 mmol),[2-chloro-4-methyl-6-(trifluoromethyl)-3-pyridyl]methanol (21) (106 mg,0.47 mmol) and sodium carbonate (150 mg, 1.42 mmol) in acetonitrile (2mL) and water (0.50 mL) was degassed under a flow of nitrogen and heatedin a microwave reactor at 140° C. for 15 min. The reaction was dilutedwith water (10 mL) and extracted into EtOAc (2×20 mL). The combinedorganic phases were dried (MgSO₄), filtered and evaporated under reducedpressure to give a crude mixture which was purified by columnchromatography (SiO₂, 4 g; gradient elution 50% EtOAc in petrol to 100%EtOAc). The desired fractions were concentrated to dryness under reducedpressure to afford the title compound as a white solid (75 mg, 42%); ¹HNMR (500 MHz, Chloroform-d) δ 7.61 (d, J=8.2 Hz, 2H), 7.52 (s, 1H), 7.37(d, J=8.1 Hz, 2H), 4.70 (s, 2H), 4.68 (s, 2H), 4.25 (s, 2H), 3.90-3.82(m, 2H), 3.36-3.27 (m, 2H), 2.63 (s, 3H); LCMS (4 minute method) productat R_(t)=0.40 min and ES⁺ m/z 381.09 [M+H]⁺

Example 10:4-[[4-[3-(Hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(42)

A mixture of4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one(9) (180 mg, 0.57 mmol), bis(triphenylphosphine)palladium(II) dichloride(20 mg, 0.030 mmol), [2-chloro-6-(trifluoromethyl)-3-pyridyl]methanol(27) (120 mg, 0.57 mmol) and sodium carbonate (180 mg, 1.70 mmol) inacetonitrile (2 mL) and water (0.5 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor at 140° C. for 15 min. Thereaction was diluted with water (30 mL) and extracted into EtOAc (2×30mL). The combined organic layers were dried (MgSO₄), filtered andevaporated under reduced pressure to give a crude mixture which waspurified by column chromatography (10 g, silica) eluting with 100%EtOAc. The desired fractions were combined and concentrated to drynessunder reduced pressure to afford the title compound as a colourless oil(119 mg, 57%); ¹H NMR (500 MHz, Chloroform-d) δ 8.16 (d, J=8.0 Hz, 1H),7.71 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H),4.77 (s, 2H), 4.68 (s, 2H), 4.26 (s, 2H), 3.86 (t, J=5.1 Hz, 2H), 3.32(t, J=5.2 Hz, 2H); LCMS (7 minute method) product at R_(t)=1.14 min andES⁺ m/z 367.10 [M+H]⁺

Example 11:2-[4-[(3-Oxomorpholin-4-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-3-carbonitrile(43)

A mixture of4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]morpholin-3-one(9) (100 mg, 0.32 mmol), bis(triphenylphosphine)palladium(II) dichloride(11 mg, 0.020 mmol), 2-chloro-6-trifluoromethylnicotinonitrile (31) (65mg, 0.32 mmol) and sodium carbonate (100 mg, 0.95 mmol) in acetonitrile(2 mL) and water (0.5 mL) was degassed under a flow of nitrogen andheated in a microwave reactor at 135° C. for 15 min. The reaction wasdiluted with water (10 mL) and extracted into EtOAc (2×20 mL). Thecombined organic layers were dried (MgSO₄), filtered and evaporatedunder reduced pressure to give a crude mixture which was purified bycolumn chromatography (SiO₂, 10 g; gradient elution 100% petrol to 50%EtOAc in petrol). The desired fractions were combined and concentratedto dryness under reduced pressure to afford the title compound as acolourless oil which solidified upon standing (63 mg, 53%); R_(f) 0.52(1:1 ethyl acetate:petrol); ¹H NMR (500 MHz, Chloroform-d) δ 8.28 (d,J=8.1 Hz, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.46 (d,J=8.0 Hz, 2H), 4.71 (s, 2H), 4.28 (s, 2H), 3.87 (t, J=5.2 Hz, 2H), 3.33(t, J=5.1 Hz, 2H); LCMS (7 minute method) product at R_(t)=3.11 min andES⁺ m/z 362.07 [M+H]⁺

Example 12:4-[[4-[3-(Hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-1,4-oxazepan-3-one(44)

A mixture of bis(triphenylphosphine)palladium(II) dichloride (11 mg,0.020 mmol), sodium carbonate (99 mg, 0.93 mmol),4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1,4-oxazepan-3-one(10) (123 mg, 0.37 mmol) and[2-chloro-4-methyl-6-(trifluoromethyl)-3-pyridyl]methanol (21) (70 mg,0.31 mmol) in acetonitrile (2 mL) and water (0.5 mL) was degassed undera flow of nitrogen and irradiated in a microwave reactor at 140° C. for15 min. The reaction was diluted with water (30 mL), then extracted intoEtOAc (2×30 mL). The combined organic layers were dried (MgSO₄),filtered and evaporated under reduced pressure to give a crude mixturewhich was purified by column chromatography (25 g, silica) eluting withEtOAc:petrol 1:1 to 100% EtOAc. The desired fractions were combined andconcentrated to dryness under reduced pressure to afford the titlecompound as a colourless oil which solidified upon standing (110 mg,87%); ¹H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J=8.1 Hz, 2H), 7.52 (s,1H), 7.38 (d, J=8.1 Hz, 2H), 4.72 (s, 2H), 4.68 (s, 2H), 4.34 (s, 2H),3.84 (t, J=5.9 Hz, 2H), 3.49-3.43 (m, 2H), 2.63 (s, 3H), 1.95-1.87 (m,2H); LCMS (4 minute method) product at R_(t)=1.72 min and ES⁺ m/z 395.12[M+H]⁺

Example 13:4-[[4-[3-(Hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]-1,4-oxazepan-5-one(45)

A mixture of bis(triphenylphosphine)palladium(II) dichloride (11 mg,0.02 mmol), sodium carbonate (99 mg, 0.93 mmol),4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-1,4-oxazepan-5-one(11) (123 mg, 0.37 mmol) and[2-chloro-4-methyl-6-(trifluoromethyl)-3-pyridyl]methanol (21) (70 mg,0.31 mmol) in acetonitrile (2 mL) and water (0.5 mL) was degassed undera flow of nitrogen and irradiated in a microwave reactor at 140° C. for15 min. The reaction was diluted with water (30 mL), then extracted intoEtOAc (2×30 mL). The combined organic layers were dried (MgSO₄),filtered and evaporated under reduced pressure to give a crude mixturewhich was purified by column chromatography (25 g, silica) eluting withEtOAc:petrol 1:1 to 100% EtOAc. The desired fractions were concentratedunder reduced pressure to afford the title compound as a colourless oilwhich solidified on standing to a gummy white solid (104 mg, 85%);

¹H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J=8.1 Hz, 2H), 7.52 (s, 1H),7.35 (d, J=7.8 Hz, 2H), 4.71 (s, 2H), 4.67 (s, 2H), 3.88-3.78 (m, 2H),3.69-3.62 (m, 2H), 3.50-3.40 (m, 2H), 2.91-2.79 (m, 2H), 2.63 (s, 3H);LCMS (4 minute method) product at R_(t)=1.66 min and ES⁺ m/z 395.13[M+H]⁺

Example 14:1-[[5-[3-(Hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidin-2-one(46)

A mixture of1-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]methyl]pyrrolidin-2-one(12) (138 mg, 0.46 mmol), bis(triphenylphosphine)palladium(II)dichloride (16.0 mg, 0.02 mmol),[2-chloro-4-methyl-6-(trifluoromethyl)-3-pyridyl]methanol (21) (103 mg,0.46 mmol) and sodium carbonate (145 mg, 1.37 mmol) in acetonitrile (2mL) and water (0.5 mL) was degassed under a flow of nitrogen and heatedin a microwave reactor at 140° C. for 15 min. The reaction was dilutedwith water (10 mL) and extracted into EtOAc (2×20 mL). The combinedorganic layers were dried (MgSO₄), filtered and evaporated under reducedpressure to give a crude mixture. The crude material was purified bycolumn chromatography (4 g, silica) eluting with 50% EtOAc in PE to 100%EtOAc then 5% MeOH in EtOAc. The desired fractions were concentrated todryness under reduced pressure to afford the title compound as a whitesolid (84 mg, 50%); ¹H NMR (500 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.11(d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J=8.1 Hz, 1H), 4.71 (s, 4H),3.48 (t, J=7.2, Hz, 2H), 2.65 (s, 3H), 2.47 (t, J=8.4 Hz, 2H), 2.14-2.04(m, 2H); LCMS (4 minute method) product at R_(t)=1.07 min and ES⁺ m/z366.22 [M+H]⁺

Example 15:2-[6-[(2-Oxopyrrolidin-1-yl)methyl]-3-pyridyl]-6-(trifluoromethyl)pyridine-3-carbonitrile(48)

A flask containing 1-[(5-bromo-2-pyridyl)methyl]pyrrolidin-2-one (7)(1.0 g, 3.92 mmol), bis(pinacolato)diboron (1.19 g, 4.7 mmol) andpotassium acetate (1.15 g, 11.8 mmol) in 1,4-dioxane (50 mL) wasevacuated and charged with nitrogen 3 times. Pd(dppf)Cl₂ (143 mg, 0.20mmol) was added and the reaction mixture was heated at 95° C. for 26hours. The reaction mixture was allowed to cool to room temperature2-chloro-6-trifluoromethylnicotinonitrile (31) (810 mg, 3.92 mmol),sodium carbonate (1.25 g, 11.8 mmol), Pd(dppf)Cl₂ (143 mg, 0.20 mmol)and water (10 mL) were added and reaction flask was evacuated andcharged with nitrogen 3 times. The reaction mixture was heated at 95° C.for 3 hours. The reaction mixture was allowed to cool to roomtemperature where it was diluted with brine (50 mL) and extracted withethyl acetate (3×100 mL). The combined organic extracts were dried overmagnesium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography (40 g silica,petrol:EtOAc, 100:0 to 0:100). The desired fractions were concentratedunder reduced pressure to afford the title compound as a pale yellow oilthat solidified upon standing to give a beige solid (1.2 g, 84%); R_(t)0.17 (100% ethyl acetate); ¹H NMR (500 MHz, Chloroform-d) δ 9.18 (d,J=2.3 Hz, 1H), 8.36-8.27 (m, 2H), 7.82 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 4.71 (s, 2H), 3.49 (t, J=7.1 Hz, 2H), 2.50 (t, J=8.1 Hz, 2H),2.09 (p, J=7.6 Hz, 2H); LCMS (4 minute method) product at R_(t)=1.78 minand ES⁺ m/z 347.23 [M+H]⁺

Example 16:1-[[4-[5-(Fluoromethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(49)

To1-[[4-[5-(hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(32) (80 mg, 0.23 mmol) in dichloromethane (4 mL), cooled in an icebath, was added [bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt %solution in toluene) (84 μL, 0.46 mmol) dropwise. The reaction wasslowly warmed to room temperature and stirred for 2 hours. More[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (84 μL, 0.46 mmol) was added and the reaction mixture stirredfor another 2 hours. The reaction mixture was cooled in an ice bath andquenched by addition of sat. aq. NaHCO₃ (5 mL), the layers wereseparated and the aqueous layer extracted with DCM (2×10 mL). Thecombined organic layers were washed with brine (30 mL), dried over MgSO₄and concentrated under reduced pressure. The crude product was purifiedby column chromatography on silica (10% EtOAc in petrol to 100% EtOAc).The desired fractions were concentrated under reduced pressure to affordthe title compound as a white solid (43 mg, 49%); ¹H NMR (500 MHz,Chloroform-d) δ 8.08 (d, J=8.4 Hz, 1H), 8.04 (d, J=7.9 Hz, 2H), 7.96 (d,J=8.3 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H), 5.67 (d, J=46.7 Hz, 2H), 4.52 (s,2H), 3.29 (t, J=7.0 Hz, 2H), 2.47 (t, J=8.1 Hz, 2H), 2.07-1.96 (m, 2H);LCMS (4 minute method) product at R_(t)=2.58 min and ES⁺ m/z 353.11[M+H]⁺

Example 17:1-[[4-[3-(Fluoromethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(50)

To a solution of1-[[4-[3-(hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(33) (66 mg, 0.18 mmol) in DCM (4 mL) at 0° C. was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (100 μL, 0.54 mmol). The reaction was slowly warmed to roomtemperature and stirred overnight. [Bis(2-methoxyethyl)amino]sulphurtrifluoride (50 wt % solution in toluene) (52 μL, 0.28 mmol) was addedand the mixture stirred for 2 hours. The reaction mixture was quenchedby addition of sat. aq. NaHCO₃ (5 mL) and the layers were separatedusing a phase separator. The organic layer was concentrated underreduced pressure and the crude product was purified by columnchromatography (SiO₂, 4 g, gradient elution: 10% EtOAc in petrol to 100%EtOAc). The desired fractions were concentrated to dryness under reducedpressure to afford the title compound as a white solid (47 mg, 71%); ¹HNMR (500 MHz, Chloroform-d) δ 7.57 (d, J=8.3, 2H), 7.55 (s, 1H), 7.36(d, J=8.3, 2H), 5.43 (d, J=48.0 Hz, 2H), 4.53 (s, 2H), 3.31 (t, J=7.1Hz, 2H), 2.63 (s, 3H), 2.47 (t, J=8.2 Hz, 2H), 2.13-1.88 (m, 2H); LCMS(4 minute method) product at R_(t)=2.58 min and ES⁺ m/z 367.08 [M+H]⁺

Example 18:1-[[4-[5-(Fluoromethyl)-2-(trifluoromethyl)pyrimidin-4-yl]phenyl]methyl]pyrrolidin-2-one(51)

To1-[[4-[5-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]phenyl]methyl]pyrrolidin-2-one(35) (62 mg, 0.18 mmol) in DCM (4 mL), cooled in an ice bath, was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (65 μL, 0.35 mmol) dropwise. The reaction was slowly warmed toroom temperature and stirred for 3 days. The reaction mixture was cooledin an ice bath and quenched by addition of sat. aq. NaHCO₃ (5 mL), thelayers were separated and the aqueous layer was extracted with DCM (2×10mL). The combined organic layers were washed with brine (30 mL), driedover MgSO₄ and concentrated under reduced pressure. The crude productwas purified by column chromatography on silica (petrol:EtOAc, gradient10:90 to 0:100). The desired fractions were concentrated under reducedpressure to afford the title compound as a white solid (61 mg, 98%); ¹HNMR (500 MHz, Chloroform-d) δ 9.06 (s, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.44(d, J=8.2 Hz, 2H), 5.53 (d, J=47.2 Hz, 2H), 4.55 (s, 2H), 3.33 (t, J=7.1Hz, 2H), 2.48 (t, J=8.1 Hz, 2H), 2.05 (p, J=7.6 Hz, 2H); LCMS (4 minutemethod) product at R_(t)=2.11 min and ES⁺ m/z 354.12 [M+H]⁺

The starting material,1-[[4-[5-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]phenyl]methyl]pyrrolidin-2-one(35) was prepared as follows:

(35)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (130 mg, 0.43 mmol), bis(triphenylphosphine)palladium(II) dichloride(15 mg, 0.02 mmol), [4-chloro-2-(trifluoromethyl)pyrimidin-5-yl]methanol(25) (92 mg, 0.43 mmol) and sodium carbonate (137 mg, 1.29 mmol) inacetonitrile (2 mL) and water (0.5 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor in at 140° C. for 15 min. Thereaction was diluted with water (30 mL) and extracted into EtOAc (2×30mL). The combined organic layers were dried (MgSO₄), filtered andevaporated under reduced pressure to give a crude mixture which waspurified by column chromatography (10 g, silica) eluting with 100%EtOAc. The desired fractions were concentrated under reduced pressure toafford the title compound as a white solid (85 mg, 56%); ¹H NMR (500MHz, Chloroform-d) δ 9.11 (s, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.40 (d,J=8.0 Hz, 2H), 4.88 (s, 2H), 4.53 (s, 2H), 3.32 (t, J=7.1 Hz, 2H), 2.47(t, J=8.2 Hz, 2H), 2.04 (p, J=7.7 Hz, 2H); LCMS (7 minute method)product at R_(t)=2.32 min and ES⁺ m/z 352.04 [M+H]⁺

Example 19:1-[[4-[3-(Fluoromethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(52)

To1-[[4-[3-(hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(36) (102 mg, 0.29 mmol) in DCM (4 mL), cooled in an ice bath, was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (107 μL, 0.58 mmol) dropwise. The reaction was slowly warmed toroom temperature and stirred for 3 days. The reaction mixture was cooledin an ice bath and quenched by addition of sat. aq. NaHCO₃ (5 mL), thelayers were separated and the aqueous layer extracted with DCM (2×10mL). The combined organic layers were washed with brine (30 mL), driedover MgSO₄ and concentrated under reduced pressure. The crude productwas purified by column chromatography on silica (petrol:EtOAc, 1:1 to100% EtOAc). The desired fractions were concentrated to dryness underreduced pressure to afford the title compound as a colourless oil (74mg, 72%); ¹H NMR (500 MHz, Chloroform-d) δ 8.10 (d, J=8.1 Hz, 1H), 7.73(d, J=8.0 Hz, 1H), 7.54 (d, J=7.4 Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 5.45(d, J=47.3 Hz, 2H), 4.53 (s, 2H), 3.31 (t, J=6.7 Hz, 2H), 2.47 (t, J=8.1Hz, 2H), 2.03 (p, J=7.5 Hz, 2H); LCMS (7 minute method) product atR_(t)=3.26 min and ES⁺ m/z 353.07 [M+H]⁺

Example 20:4-[[4-[3-(Fluoromethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(53)

To a solution of4-[[4-[3-(hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(41) (40 mg, 0.11 mmol) in DCM (4 mL) at 0° C. was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (58 μL, 0.32 mmol). The reaction was slowly warmed to roomtemperature and stirred overnight. More[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (30 μL, 0.16 mmol) was added and the reaction was stirred foranother 2 hours. The reaction mixture was quenched by addition of sat.aq. NaHCO₃ (5 mL), the layers were separated using a phase separator andthe organic layer was concentrated under reduced pressure. The crudeproduct was purified by column chromatography (SiO₂, 4 g, gradientelution: 10% EtOAc in petrol to 100% EtOAc). The desired fractions wereconcentrated to dryness under reduced pressure to afford the titlecompound as a white solid (25 mg, 62%); ¹H NMR (500 MHz, Chloroform-d) δ7.62-7.57 (d, J=7.7 Hz, 2H), 7.56 (s, 1H), 7.40 (d, J=7.7 Hz, 2H), 5.43(d, J=47.6 Hz, 2H), 4.70 (s, 2H), 4.27 (s, 2H), 3.87 (t, J=5.4 Hz, 2H),3.33 (t, J=5.2 Hz, 2H), 2.63 (s, 3H); LCMS (4 minute method) product atR_(t)=2.44 min and ES⁺ m/z 383.10 [M+H]⁺

Example 21:4-[[4-[3-(Fluoromethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(54)

To4-[[4-[3-(hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(42) (80 mg, 0.22 mmol) in DCM (4 mL), cooled in an ice bath, was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (243 μL, 0.66 mmol) dropwise. The reaction was slowly warmed toroom temperature and stirred for 3 days. The reaction mixture was cooledin an ice bath and quenched by addition of sat. aq. NaHCO₃ (5 mL), thelayers were separated and the aqueous layer extracted with DCM (2×10mL). The combined organic layers were washed with brine (30 mL), driedover MgSO₄ and concentrated under reduced pressure. The crude productwas purified by column chromatography on silica (50% EtOAc in petrol to100% EtOAc). The desired fractions were combined and concentrated todryness under reduced pressure to afford the title compound as acolourless oil (74 mg, 92%); R_(f) 0.28 (1:1 ethyl acetate:petrol); ¹HNMR (500 MHz, Chloroform-d) δ 8.10 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.1 Hz,1H), 7.55 (d, J=8.2 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 5.45 (d, J=47.2 Hz,2H), 4.70 (s, 2H), 4.27 (s, 2H), 3.87 (t, J=5.2 Hz, 2H), 3.32 (t, J=5.1Hz, 2H); LCMS (4 minute method) product at R_(t)=0.56 min and ES⁺ m/z369.07 [M+H]⁺

Example 22:1-[[5-[3-(Fluoromethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidin-2-one(55)

To a solution of1-[[5-[3-(hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidin-2-one(46) (70 mg, 0.19 mmol) in DCM (4 mL) at 0° C. was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (70 μL, 0.38 mmol). The reaction was slowly warmed to roomtemperature and stirred overnight. The reaction mixture was cooled in anice bath and quenched by addition of sat. aq. NaHCO₃ (5 mL), the layerswere separated and the aqueous layer extracted with DCM (2×10 mL). Thecombined organic layers were washed with brine (30 mL), dried over MgSO₄and concentrated under reduced pressure. The crude product was purifiedby column chromatography (SiO₂, 4 g, gradient elution: 50% EtOAc inpetrol to 100% EtOAc). The desired fractions were concentrated todryness under reduced pressure to afford the title compound as a whitesolid (30 mg, 43%); ¹H NMR (500 MHz, Chloroform-d) δ 8.79 (d, J=2.3 Hz,1H), 7.98 (dd, J=8.0, 2.2 Hz, 1H), 7.61 (s, 1H), 7.44 (d, J=8.0 Hz, 1H),5.42 (d, J=47.6 Hz, 2H), 4.70 (s, 2H), 3.48 (t, J=7.1 Hz, 2H), 2.65 (s,3H), 2.48 (t, J=8.1 Hz, 2H), 2.08 (p, J=7.2 Hz, 2H); LCMS (4 minutemethod) product at R_(t)=1.71 min and ES⁺ m/z 368.22 [M+H]⁺

Example 23:1-[[5-[3-(Fluoromethyl)-6-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidin-2-one(56)

To1-[[5-[3-(hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidin-2-one(47) (44 mg, 0.13 mmol) in DCM (4 mL), cooled in an ice bath, was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (46 μL, 0.25 mmol) dropwise. The reaction was slowly warmed toroom temperature and stirred for 3 days. The reaction mixture was cooledin an ice bath and quenched by addition of sat. aq. NaHCO₃ (5 mL), thelayers were separated and the aqueous layer extracted with DCM (2×10mL). The combined organic layers were washed with brine (30 mL), driedover MgSO₄ and concentrated under reduced pressure. The crude productwas purified by column chromatography on silica (petrol:EtOAc, gradient10:90 to 0:100). The desired fractions were combined and concentrated todryness under reduced pressure to afford the title compound as acolourless oil (28 mg, 63%); ¹H NMR (500 MHz, Chloroform-d) δ 8.79 (d,J=8.1 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.99 (dd, J=7.9, 2.3 Hz, 1H),7.79 (d, J=8.0 Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 5.46 (d, J=47.2 Hz, 2H),4.71 (s, 2H), 3.49 (t, J=7.1 Hz, 2H), 2.48 (t, J=8.1 Hz, 2H), 2.13-2.03(m, 2H); LCMS (4 minute method) product at R_(t)=1.63 min and ES⁺ m/z354.22 [M+H]⁺

The starting material1-[[5-[3-(Hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]-2-pyridyl]methyl]pyrrolidin-2-one(47) was prepared as follows:

(47)

A mixture of1-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]methyl]pyrrolidin-2-one(12) (95 mg, 0.31 mmol), bis(triphenylphosphine)palladium(II) dichloride(11 mg, 0.020 mmol), [2-chloro-6-(trifluoromethyl)-3-pyridyl]methanol(27) (66 mg, 0.31 mmol) and sodium carbonate (100 mg, 0.94 mmol) inacetonitrile (2 mL) and water (0.5 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor at 140° C. for 15 min. Thereaction was diluted with water (30 mL) and extracted into EtOAc (2×30mL). The combined organic layers were dried (MgSO₄), filtered andevaporated under reduced pressure to give a crude mixture which waspurified by column chromatography (10 g, silica) eluting with MeOH:EtOAc(0:100 to 5:95). The desired fractions were combined and concentrated todryness under reduced pressure to afford the title compound as acolourless oil which solidified on standing to an off-white solid (59mg, 53%); ¹H NMR (500 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.20 (d, J=8.0Hz, 1H), 8.00 (dd, J=8.3, 2.2 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.42 (d,J=8.1 Hz, 1H), 4.78 (s, 2H), 4.68 (s, 2H), 3.47 (t, J=7.1 Hz, 2H), 2.48(t, J=8.1 Hz, 2H), 2.13-2.04 (m, 2H); LCMS (4 minute method) product atR_(t)=0.58 min and ES⁺ m/z 352.23 [M+H]⁺

Example 24:4-Methyl-2-[4-[(3-oxomorpholin-4-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-3-carbonitrile(57)

To a solution of4-[[4-[3-(hydroxymethyl)-4-methyl-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]morpholin-3-one(41) (30 mg, 0.079 mmol) in acetonitrile (0.45 mL) and water (0.050 mL)was added (diacetoxyiodo)benzene (55 mg, 0.17 mmol), TEMPO (0.62 mg,0.0039 mmol) and ammonium acetate (24 mg, 0.32 mmol). The reactionmixture was stirred at room temperature for 18 hours before beingconcentrated under reduced pressure. The reaction mixture was dilutedwith deionised water (10 mL) and extracted with ethyl acetate (3×10 mL).The combined organic extracts were dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (5 g silica, petrol:EtOAc, 100:0 to 0:100). Thedesired fractions were concentrated under reduced pressure to afford thetitle compound as a yellow oil (15 mg, 48%); R_(f) 0.24 (1:1 ethylacetate:petrol); ¹H NMR (500 MHz, Chloroform-d) δ 7.95 (d, J=8.2 Hz,2H), 7.63 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 4.72 (s, 2H), 4.29 (s, 2H),3.94-3.81 (m, 2H), 3.38-3.26 (m, 2H), 2.75 (s, 3H); LCMS (4 minutemethod) product at R_(t)=0.57 min and ES⁺ m/z 376.06 [M+H]⁺

Example 25:1-[[4-[4-(Hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(61)

To a solution of2-[4-[(2-oxopyrrolidin-1-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-4-carbaldehyde(60) (38 mg, 0.11 mmol) in methyl alcohol (2 mL) at room temperature wasadded sodium borohydride (10 mg, 0.26 mmol). The reaction mixture wasstirred at room temperature for 3 hours before being concentrated underreduced pressure. The residue was dissolved in deionised water (3 mL)and DCM (3 mL). The phases were separated and the aqueous phase wasextracted with DCM (3×5 mL). The combined organic extracts were driedover magnesium sulfate, filtered and concentrated under reducedpressure. The residue was purified by flash column chromatography (5 gsilica, EtOAc:MeOH, 100:0 to 95:5). The desired fractions wereconcentrated under reduced pressure to afford the title compound as awhite solid (10 mg, 25%); R_(f) 0.14 (100% ethyl acetate); ¹H NMR (500MHz, Chloroform-d) δ 8.01 (d, J=8.2 Hz, 2H), 7.89 (s, 1H), 7.61 (s, 1H),7.33 (d, J=8.1 Hz, 2H), 4.88 (d, J=1.9 Hz, 2H), 4.49 (s, 2H), 3.28 (t,J=7.1 Hz, 2H), 2.71 (s, 1H), 2.46 (t, J=8.1 Hz, 2H), 2.11-1.91 (m, 2H);LCMS (4 minute method) product at R_(t)=1.40 min and ES⁺ m/z 351.09[M+H]⁺.

The starting material (60) was prepared as follows:

2-Chloro-6-(trifluoromethyl)pyridine-4-carbaldehyde (59)

To a solution of 2-chloro-6-trifluoromethylpyridine (58) (2.0 g, 11.0mmol) in tetrahydrofuran (40 mL) at room temperature was added2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloridecomplex solution (1 M in THF/toluene) (13.2 mL, 13.2 mmol) dropwise.After stirring for 1 hour at room temperature the dark reaction mixturewas cooled to −78° C. and a solution of N,N-dimethylformamide (1.71 mL,22.0 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reactionmixture was stirred for 1 hour at −78° C. and then allowed to warm toroom temperature where it was stirred for a further 16 hours. Thereaction mixture was quenched with saturated aqueous NH₄Cl (75 mL) andextracted with ethyl acetate (3×75 mL). The combined organic extractswere dried over magnesium sulfate, filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography (25 g silica, petrol:EtOAc, 100:0 to 90:10). The desiredfractions were concentrated under reduced pressure to afford the titlecompound as an orange oil (830 mg, 34%); R_(f) 0.21 (5:95 MeOH:ethylacetate); ¹H NMR (500 MHz, Chloroform-d) δ 10.12 (s, 1H), 8.03 (s, 1H),7.95 (s, 1H); LCMS (4 minute method) product at R_(t)=2.27 min and ES⁺m/z 242.02, 244.01 [M+MeOH+H]⁺ (Cl isotope)

2-[4-[(2-Oxopyrrolidin-1-yl)methyl]phenyl]-6-(trifluoromethyl)pyridine-4-carbaldehyde(60)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (100 mg, 0.33 mmol), bis(triphenylphosphine)palladium(II) dichloride(12 mg, 0.020 mmol), 2-chloro-6-(trifluoromethyl)pyridine-4-carbaldehyde(59) (70 mg, 0.33 mmol) and sodium carbonate (106 mg, 1.00 mmol) inacetonitrile (4 mL) and water (1 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor at 145° C. for 20 min. Thereaction was diluted with water (15 mL) and extracted into EtOAc (3×20mL). The combined organic extracts were dried over magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography (10 g silica, EtOAc:MeOH, 100:0to 95:5). The desired fractions were concentrated under reduced pressureto afford the title compound as a pale yellow oil (65 mg, 48%); R_(f)0.44 (5:95 MeOH:ethyl acetate); ¹H NMR (500 MHz, Chloroform-d) δ 10.20(s, 1H), 8.31 (s, 1H), 8.10 (d, J=8.2 Hz, 2H), 8.00 (s, 1H), 7.41 (d,J=8.2 Hz, 2H), 4.54 (s, 2H), 3.31 (t, J=7.0 Hz, 2H), 2.47 (t, J=8.1 Hz,2H), 2.10-1.96 (m, 2H); LCMS (4 minute method) product at R_(t)=2.33 minand ES⁺ m/z 349.06 [M+H]⁺

Example 26:1-[[4-[4-(Methoxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(62)

To a solution of1-[[4-[4-(hydroxymethyl)-6-(trifluoromethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(61) (17 mg, 0.05 mmol) in tetrahydrofuran (1 mL) and was added sodiumhydride (60% in oil) (5.6 mg, 0.15 mmol). The yellow reaction mixturewas stirred for 30 minutes before the addition of iodomethane (9.0 μL,0.15 mmol). The reaction mixture was stirred at room temperature for 18hours before being quenched with MeOH (100 μL) and then concentratedunder reduced pressure. The residue was purified by flash columnchromatography (5 g silica, petrol:EtOAc, 100:0 to 0:100). The desiredfractions were concentrated under reduced pressure to afford the titlecompound as a yellow gum (11 mg, 56%); R_(t) 0.16 (100% ethyl acetate);¹H NMR (500 MHz, Chloroform-d) δ 8.04 (d, J=8.2 Hz, 2H), 7.86 (s, 1H),7.57 (s, 1H), 7.37 (d, J=8.1 Hz, 2H), 4.60 (s, 2H), 4.52 (s, 2H), 3.51(s, 3H), 3.29 (t, J=7.1 Hz, 2H), 2.47 (t, J=8.1 Hz, 2H), 2.02 (p, J=7.5Hz, 2H); LCMS (4 minute method) product at R_(t)=3.01 min and ES⁺ m/z365.09 [M+H]⁺

Example 27:1-[[4-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl]phenyl]methyl]pyrrolidin-2-one(67)

A mixture of acetic acid; 4-[(2-oxopyrrolidin-1-yl)methyl]benzamidine(66) (99 mg, 0.36 mmol), (E)-1,1,1-trifluoro-4-methoxy-3-penten-2-one(50 mg, 0.30 mmol) and sodium ethoxide (24 mg, 0.36 mmol) in ethanol(500 μL) were heated at 70° C. for 18 hours. The reaction mixture wasconcentrated under reduced pressure and the residue was purified byflash column chromatography (10 g silica, petrol:EtOAc, 100:0 to 0:100).The desired fractions were concentrated under reduced pressure to affordthe title compound as a colourless oil that solidified upon standing (75mg, 74%); R_(f) 0.25 (8:2 ethyl acetate:petrol); ¹H NMR (500 MHz,Chloroform-d) δ 8.46 (d, J=8.2 Hz, 2H), 7.38-7.34 (m, 3H), 4.53 (s, 2H),3.28 (t, J=7.1 Hz, 2H), 2.69 (s, 3H), 2.46 (t, J=8.1 Hz, 2H), 2.01 (p,J=7.5 Hz, 2H); LCMS (4 minute method) product at R_(t)=0.66 min and ES⁺m/z 336.11 [M+H]⁺

The starting material (66) was prepared as follows:

4-[(2-Oxopyrrolidin-1-yl)methyl]benzonitrile (64)

To a solution of pyrrolidin-2-one (0.79 mL, 10.2 mmol) inN,N-dimethylformamide (10 mL) at 0° C. was added sodium hydride (60% inoil) (489 mg, 12.2 mmol) portionwise and the mixture was left stirringat 0° C. for about 30 min. Then 4-(bromomethyl)benzonitrile (63) (2.0 g,10.2 mmol) was added portionwise over 5 min. and the reaction mixtureallowed to warm to room temperature and stirred for 16 hours. Thereaction mixture was quenched with water and diluted with EtOAc (100mL). The organic layer was washed with brine (3×100 mL), dried (MgSO₄)and solvent evaporated under reduced pressure, the crude was purified byflash chromatography (Biotage, 25 g) eluting with EtOAc:petrol (50:50 to100:0). Fractions containing product were combined and evaporated underreduced pressure to afford the title compound as a white solid (1.72 g,82%); ¹H NMR (500 MHz, Chloroform-d)) δ 7.63 (d, J=8.2 Hz, 2H), 7.36 (d,J=8.3 Hz, 2H), 4.51 (s, 2H), 3.29 (t, J=7.1 Hz, 2H), 2.47 (t, J=8.1 Hz,2H), 2.05 (p, J=7.5 Hz, 2H); LCMS (7 minute method) product atR_(t)=1.27 min and ES⁺ m/z 201.11 [M+H]⁺

N′-Hydroxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzamidine (65)

To 4-[(2-oxopyrrolidin-1-yl)methyl]benzonitrile (64) (660 mg, 3.30 mmol)in ethanol (10 mL) was added hydroxylamine hydrochloride (687 mg, 9.89mmol) followed by potassium carbonate (1.37 g, 9.89 mmol) and thereaction mixture was heated at refluxed for 16 hours. Volatiles wereremoved under reduced pressure, the residue was diluted with brine (50mL) and extracted extensively into DCM (5×50 mL). The combined organiclayers were dried (MgSO₄), filtered and evaporated under reducedpressure to afford the title compound as a white foam (745 mg, 76%); ¹HNMR (500 MHz, DMSO-d₆) δ 9.58 (s, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.20 (d,J=8.1 Hz, 2H), 5.75 (s, 2H), 4.36 (s, 2H), 3.22 (t, J=7.1 Hz, 2H), 2.29(t, J=8.0 Hz, 2H), 1.98-1.86 (m, 2H); LCMS (4 minute method) product atR_(t)=0.31 min and ES⁺ m/z 234.12 [M+H]⁺

Acetic Acid; 4-[(2-oxopyrrolidin-1-yl)methyl]benzamidine (66)

To N′-hydroxy-4-[(2-oxopyrrolidin-1-yl)methyl]benzamidine (65) (740 mg,3.17 mmol) in acetic acid (20 mL) was added acetic anhydride (0.45 mL,4.76 mmol). The mixture was stirred at for 10 min, then 10% palladium oncarbon (101 mg) was added and the mixture was hydrogenated (1 barhydrogen) at 25° C. for 24 hours. The catalyst was filtered off andwashed with acetic acid/methanol. The filtrate was evaporated underreduced pressure to afford the title compound as a beige solid (945 mg,84%); ¹H NMR (500 MHz, DMSO-d₆) δ 7.76 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.0Hz, 2H), 4.45 (s, 2H), 3.30-3.19 (m, 2H), 2.34-2.24 (m, 2H), 2.01-1.89(m, 2H), 1.81 (s, 3H); LCMS (7 minute method) product at R_(t)=0.45 minand ES⁺ m/z 218.23 [M+H]⁺

Example 28:1-[[4-[6-(Difluoromethyl)-3-(hydroxymethyl)-2-pyridyl]phenyl]methyl]pyrrolidin-2-one(74)

A mixture of1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]pyrrolidin-2-one(8) (185 mg, 0.61 mmol), bis(triphenylphosphine)palladium(II) dichloride(21 mg, 0.03 mmol), [2-chloro-6-(difluoromethyl)-3-pyridyl]methanol (73)(119 mg, 0.61 mmol) and sodium carbonate (195 mg, 1.84 mmol) inacetonitrile (3 mL) and water (1 mL) was degassed under a flow ofnitrogen and heated in a microwave reactor at 135° C. for 15 min. Thereaction was diluted with water (10 mL) and extracted into EtOAc (2×20mL). The organics were dried (MgSO₄), filtered and concentrated underreduced pressure to give a crude mixture which was purified by columnchromatography (SiO₂, 10 g; gradient elution 10% EtOAc in petrol to 100%EtOAc). The desired fractions were combined and concentrated underreduced pressure to afford the title compound as a light yellow solid(105 mg, 49%); ¹H NMR (500 MHz, Chloroform-d) δ 8.13 (d, J=8.0 Hz, 1H),7.67 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H),6.68 (t, J=55.4 Hz, 1H), 4.73 (s, 2H), 4.49 (s, 2H), 3.30 (t, J=7.1 Hz,2H), 2.45 (t, J=8.1 Hz, 2H), 2.03-1.97 (m, 2H); LCMS (4 minute method)product at R_(t)=1.01 min and ES⁺ m/z 333.09 [M+H]⁺

The starting material (73) was prepared as follows:

Methyl 2-chloro-6-methyl-pyridine-3-carboxylate (69)

To a solution of 2-chloro-6-methylpyridine-3-carboxylic acid (68) (5.0g, 29.1 mmol) in N,N-dimethylformamide (50 mL) was added potassiumcarbonate (12.1 g, 87.4 mmol) followed by iodomethane (5.4 mL, 87.4mmol) and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with EtOAc (50 mL) and thesuspension was filtered. The filtrate was then concentrated down and theremaining residue was taken up in EtOAc (150 mL). The solution waswashed with water (75 mL) and brine (75 mL). The organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure to affordthe title compound leave a yellow oil (5.0 g, 91%); ¹H NMR (500 MHz,Chloroform-d) δ 8.08 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 3.94 (s,3H), 2.59 (s, 3H); LCMS (4 minute method) product at R_(t)=1.14 min andES⁺ m/z 186.19 [M+H]⁺

Methyl 2-chloro-6-[(E)-2-(dimethylamino)vinyl]pyridine-3-carboxylate(70)

To a mixture of methyl 2-chloro-6-methyl-pyridine-3-carboxylate (69)(5.0 g, 26.9 mmol) in N,N-dimethylformamide (25 mL) was addedN,N-dimethylformamide dimethyl acetal (8.9 mL, 67.4 mmol) and thereaction mixture was heated to 120° C. overnight. N,N-dimethylformamidedimethyl acetal (4.3 mL, 32.3 mmol) was added and heating continued at120° C. for another 3 hours. The mixture was cooled to room temperatureand concentrated under reduced pressure. The orange residue was taken upin EtOAc (100 mL) and the solution was washed with water (80 mL) andbrine (80 mL). The organic layer was dried (MgSO₄), filtered andconcentrated under reduced pressure to afford the title compound as anorange oil (6.2 g, 86%); ¹H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J=8.2Hz, 1H), 7.68 (d, J=12.8 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 5.10 (d,J=12.8 Hz, 1H), 3.88 (s, 3H), 2.96 (s, 6H); LCMS (4 minute method)product at R_(t)=0.92 min and ES⁺ m/z the desired mas ion was notobserved.

Methyl 2-chloro-6-formyl-pyridine-3-carboxylate (71)

A solution of sodium periodate (9.95 g, 46.5 mmol) in water (25 mL) wasadded to a solution of methyl2-chloro-6-[(E)-2-(dimethylamino)vinyl]pyridine-3-carboxylate (70) (5.6g, 23.2 mmol) in tetrahydrofuran (80 mL) at room temperature. Themixture was stirred for about 2 hours and then quenched with an aqueoussolution of sodium thiosulfate. The mixture was filtered and thefiltrate was diluted with more water (100 mL) and extracted with EtOAc(2×100 mL). The combined organic layers were washed with brine (50 mL),dried (MgSO₄), filtered and concentrated under reduced pressure toafford an orange solid. (3.9 g). The crude material was purified twiceby column chromatography (SiO₂, 25 g; gradient elution 100% petrol to50% EtOAc in petrol). The desired fractions were combined andconcentrated under reduced pressure to afford the title compound as anorange solid (838 mg, 14%); ¹H NMR (500 MHz, Chloroform-d) δ 10.04 (s,1H), 8.31 (d, J=7.8 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 4.01 (s, 3H); LCMS(4 minute method) product at R_(t)=0.97 min and ES⁺ m/z 200.17 [M+H]⁺

Methyl 2-chloro-6-(difluoromethyl)pyridine-3-carboxylate (72)

To a solution of methyl 2-chloro-6-formyl-pyridine-3-carboxylate (71)(200 mg, 1.0 mmol) in DCM (5 mL) at 0° C. was added[bis(2-methoxyethyl)amino]sulphur trifluoride (50 wt % solution intoluene) (0.46 mL, 2.51 mmol). The reaction mixture was allowed to warmup to room temperature and was stirred overnight. The reaction mixturewas quenched with sat. aq. NaHCO₃, the layers were separated and theaqueous layer was extracted with DCM (2×15 mL). The combined organiclayers were washed with brine (25 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure to leave a light yellow oil. Thisoil was purified by column chromatography (10 g, SiO₂; gradient elution100% petrol to 80% EtOAc in petrol). The desired fractions were combinedand concentrated under reduced pressure to afford the title compound asa white solid (113 mg, 48%); ¹H NMR (500 MHz, Chloroform-d) δ 8.31 (d,J=7.9 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 6.61 (t, J=54.9 Hz, 1H), 4.00 (s,3H); LCMS (4 minute method) product at R_(t)=2.30 min and ES⁺ m/z 222.09[M+H]⁺

2-Chloro-6-(difluoromethyl)-3-pyridyl]methanol (73)

To a solution of methyl2-chloro-6-(difluoromethyl)pyridine-3-carboxylate (72) (170 mg, 0.77mmol) in DCM (15 mL) at 0° C. was added diisobutylaluminum hydride (1 Msolution in toluene) (2.3 mL, 2.3 mmol) and the mixture was slowlyallowed to warm to room temperature. After 2 hours the reaction mixturewas quenched with sat. aq. Rochelle's salt and stirred for 30 min beforebeing concentrated under reduced pressure. The product was thenextracted into DCM (3×20 mL). The combined organic layers were washedwith brine (30 mL), dried over (MgSO₄), filtered and then concentratedunder reduced pressure to afford the title compound as a clear oil whichsolidified upon standing (130 mg, 83%); ¹H NMR (500 MHz, Chloroform-d) δ8.07 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 6.60 (t, J=55.2 Hz, 1H),4.84 (s, 2H); LCMS (4 minute method) product at R_(t)=0.70 min and ES⁺m/z 194.13 [M+H]⁺

Biological Data AMPA Calcium Ion Influx Assay

The ability of the compounds of the invention to potentiate glutamatereceptor-mediated response was determined using fluorescentcalcium-indicator dye.

96 well plates were prepared containing confluent monolayer of HEK 293cells stably expressing human GluR2 flip (unedited) AMPA receptorsubunit (obtained from GlaxoSmithKline). These cells form functionalhomotetrameric AMPA receptors. The tissue culture medium in the wellswas discarded and the wells were each washed three times with standardbuffer for the cell line (145 μM NaCl, 5 mM KCl, 1 mM MgCl₂, 2 mM CaCl₂,20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES),5.5 mM glucose, pH7.3). The plates were then incubated for 60 minutes inthe dark with 2 μM Calcium 6 dye (Molecular Devices). After incubation,each well was washed three times with buffer (80 μl).

Compounds of the invention were dissolved in dimethylsulfoxide (DMSO) ata stock concentration of 10 mM. These solutions were further dilutedwith DMSO. Each dilution (4 μl) to another compound plate and buffer(200 μl) was added. An agonist stimulus plate (glutamate) was preparedby dissolving sodium glutamate in water to give a concentration of 100mM. This solution was diluted with buffer to give a final concentrationof 500 μM and dispensed into another 96 well plate (200 μl/well).

The cell plate was then transferred to a fluorescence imaging platereader such as the Flexstation 3 (Molecular Devices). A baselinefluorescence was taken over a 10 to 240 second period and then 40 μlfrom each plate containing a compound of the invention made up instandard buffer solution was added. Volumes were chosen to give a finalconcentration range of 40 μM to 4 μM. The fluorescence was then readover a 4 minute period. The activities of the compounds were determinedby measuring peak fluorescence after the last addition. The activity canalso be expressed relative to the fluorescence increase induced bycyclothiazide at their maximum response (i.e. greater than 40 μM).

Intrinsic Clearance (CLi)

The in-vitro intrinsic clearance of certain compounds was measured inrat and human hepatocytes using the following assay.

5 μL microsomes (20 mg/ml, Corning BV) diluted into 95 μL PBS (pH 7)containing 0.2% DMSO and 4 μM test article were incubated at 37° C.shaking at 1000 rpm prior the addition of 100 μL of pre-warmed 4 mMNADPH in PBS (final concentrations: 0.5 mg/mL microsomes, 2 μM testarticle, 0.1% DMSO and 2 mM NADPH). After mixing thoroughly the T=0sample (40 μL) was immediately quenched into ice cold methanolcontaining 2 μM internal standard (Carbemazapine). Three further sampleswere quenched in the same way at 3, 9 and 30 min. Samples were incubatedon ice for 30 min before centrifugation at 4000 rpm+ for 200 min. Thesupernatant was analysed via LCMS and the test article:carbemazapinepeak area ratios calculated to determine the rate of substratedepletion.

Biological Data

The table below shows the mean % response in the AMPA calcium ion influxassay described above at a test compound concentration of 10 μM

Example # Mean % response (Compound #) Structure at 10 μM Example 1 (32)

33 Example 2 (33)

41 Example 3 (34)

4 Example 4 (36)

9 Example 5 (37)

99 Example 6 (38)

29 Example 7 (39)

21 Example 8 (40)

14 Example 9 (41)

14 Example 10 (42)

3 Example 11 (43)

11 Example 12 (44)

9 Example 13 (45)

5 Example 14 (46)

5 Example 15 (48)

6 Example 16 (49)

28 Example 17 (50)

111 Example 18 (51)

5 Example 19 (52)

70 Example 20 (53)

112 Example 21 (54)

16 Example 22 (55)

93 Example 23 (56)

9 Example 24 (57)

39 Example 25 (61)

8 Example 26 (62)

4 Example 27 (67)

27 Example 28 (74)

2

Electrophysiology Assay

The ability of the compounds of the invention to increase AMPA mediatedcurrents was demonstrated using in-vitro whole cell voltage clampelectrophysiology.

Primary hippocampal neuronal cultures were prepared using an in-houseprocedure similar to Nunez (JoVE. 2008, DOI: 10.3791/895) from rat pups(P0-P1) and electrophysiology recordings were made 2-4 weeks postharvesting.

Dissociated neurons were plated in culture dishes containing coverslipscoated with poly-D-lysine and laminin, and maintained at 37° C. with 5%CO₂ in a humidified atmosphere. Cells were cultured in neurobasal mediasupplemented with foetal bovine serum (2%), glucose 45% (0.4%),Na-pyruvate (1 mM), HEPES (10 mM), serum free B-27 supplement 50× (1%),penicillin-streptomycin (1%) and glutamax (1%). Cells were fed on day 3,day 5 and then every three days by replacing half of the volume withfreshly prepared media. From day 5 the media was supplemented withcytosine arabinoside (Ara-C, 4 μg/ml) to prevent glial cellproliferation.

Test compounds were dissolved in dimethylsulfoxide (DMSO) to produce 10mM stock solutions. On the day of recordings they were diluted into theextracellular recording solution to the desired final concentrationwhile maintaining a final DMSO concentration of 0.3% (v/v). Theextracellular solution (145 mM NaCl, 2.5 mM KCl, 1.2 mM MgCl₂, 1.5 mMCaCl₂, 10 mM HEPES, 10 mM D-Glucose, 310 mOsm, pH adjusted to 7.35 withNaOH) was supplemented with the following ion channel blockers at thetime of recordings: TTX (1 μM), (−)-bicuculline methobromide (10 μM),(+)-MK801 maleate (0.5 μM), strychnine (1 μM).

For recordings, coverslips were transferred to a 200 μl volume recordingRSC200 system (RSC200, Biologics) chamber that was continuously perfusedwith extracellular buffer at a regulated flow rate (1.5 ml/min). Wholecell patch-clamp configuration was obtained using borosilicate glasselectrodes pipettes of 3-8 MO resistance when filled with anintracellular solution containing 80 mM CsCl, 80 mM CsF, 10 mM HEPES(300 mOsm, pH adjusted to 7.3 using CsOH). Currents were recorded atroom temperature using a patch-clamp amplifier (Axopatch 200B) with 2kHz low-pass filter and subsequently digitized at 50 kHz with a Digidata1322A/D and pClamp 10 data acquisition software (Axon Instruments, USA).

Clamped cells were kept at a holding potential of −70 mV and currentsrecorded in 15 s sweeps. Current responses were evoked by 3 sapplication of 30 μM s-AMPA every 57 s before and during co-applicationof the test compound. Only cells with stable currents to fourapplications of s-AMPA alone (<20% variation between first and fourthapplications) were used for compound testing. Compounds were tested atvariable concentrations between 10 and 10000 nM, with only oneconcentration applied per cell.

Data were analysed by evaluating the changes of three parameters (areaunder the curve, peak and stable AMPA activated current) in the presenceof the test compound expressed as percentage of the same parametersbefore compound additions. The minimum effective concentration was theconcentration of test compound that resulted in a statisticallysignificant change in the parameter being monitored (area under thecurve, peak and stable AMPA activated current).

Compounds UoS26495, UoS21365, UoS26417, UoS21372, UoS21424, UoS21472,UoS26366 and UoS26478 exemplified herein were tested in this assay had aminimum effective concentration (MEC) of less than 10 μM.

In-Vivo Assays NOR Assay

Certain of the exemplified compounds (UoS21365 and UoS26478) have beentested in the Novel Object Recognition (NOR) assay analogous to thatdescribed in Ennaceur et al., (Behav. Brain Res. 1988, 31, 47-59) andexhibit a minimal effective dose of less than 10 mg/kg.

Sub-Chronic PCP-Induced Reversal Learning

The reversal learning task is an in-vivo assay for cognitive functionthat may be of particular relevance to schizophrenia (Abdul-Monim etal., Behav. Brain Res. 2006, 169, 263-273). Rats are trained overseveral weeks to press a lever contingent with a light cue for a foodreward (either lever under a light, or lever not under a light). For thereversal task, rats are first given a 30 min operant training sessionwith a constant contingency relative to the light cue. This is followedby a 5 min session called the “initial task”, in which the contingencyis the same as for the prior operant session. After the initial taskthere is a 5 min “reversal task” in which the contingency is reversed.Responses on correct and incorrect levers in the initial and reversaltask are recorded. Once performance is stable the training is stoppedand a cognitive deficit is induced in the rats via sub-chronicadministration of phencyclidine (PCP) followed by at least 7-dayswashout (as a control some rats receive saline instead of PCP). Thecognitive effects of drugs can be tested with acute administration ofthe test drug before the reversal task, with initial and reversalsessions as above. Risperidone, an atypical antipsychotic, is used as apositive control that is known to attenuate the cognitive deficit.

One of the compounds exemplified herein, “UoS26478” was tested acutelyat doses of 3.0, 10 and 30 mg/kg (per oral, 30 min ptt) compared torisperidone (0.1 mg/kg, i.p, 60 min ptt) in sub-chronic phencyclidine(scPCP) treated rats (2 mg/kg, i.p. twice daily for seven days, followedby at least a 7-day washout period) to restore performance in thereversal learning task.

Results are shown in FIG. 1. The data in FIG. 1 shows mean±s.e.m. %correct lever responses (n=9-10) and were analysed by ANOVA and post-hocLSD test. The compound of the invention, UoS26478, showed a significantincrease at 10 and 30 mg/kg in correct responses compared to scPCP plusvehicle in the reversal phase; #P<0.05-##P<0.01. The compound at 3mg/kg, and vehicle, showed a significant reduction in percentage ofcorrect responses in the reversal phase compared with the rats which hadnot had scPCP induced cognitive deficit (scSaline+veh)*P<0.05, **P<0.01.

1. A compound of the formula (I), or a pharmaceutically acceptable saltthereof:

A¹ is N or CR¹; A² is N or CR³; and wherein only a single one of A¹ andA² may be N; R¹ is selected from the group consisting of: H, CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A1) and—C(O)NR^(A1)R^(B1); R² is selected from the group consisting of: H, CN,C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OR^(A2) and—C(O)NR^(A2)R^(B2); R³ is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₃₋₄ cycloalkyl, —C₁₋₄ alkyl-OH and —C(O)NR^(A3)R^(B3); each X isindependently H or F, provided at least one X is F; B¹ and B² areindependently CH or N; R⁴ is halo; X¹ is O or CH₂; R^(A1), R^(B1),R^(A2), R^(B2), R^(A3) and R^(B3) are each independently selected from:H and C₁₋₄ alkyl; a is an integer selected from 0, 1 or 2; b is aninteger selected from 0, 1 or 2; a+b is 0, 1, 2 or 3; and n is 0, 1 or2; with the following provisos: (i) R¹, R² and R³ are not all H; (ii)when A¹ is N, at least one of R² and R³ is C₁₋₄ alkyl or C₁₋₄ haloalkyl;(iii) when A² is N, at least one of R¹ and R² is C₁₋₄ alkyl or C₁₋₄haloalkyl; (iv) when A¹ is CR¹, R¹ is —CH₂OH and B¹ is N, then R² is notH; and (v) when A¹ is CR¹, R¹ is —CN and B² is N, then R² is not H. 2.The compound of claim 1, wherein the group —CX₃ is —CF₃.
 3. The compoundof claim 1 or claim 2, wherein B² is CH.
 4. The compound of any ofclaims 1 to 3, wherein the group of the formula:

is selected from:


5. The compound of claim 1, wherein the compound is of the formula(III), or a pharmaceutically acceptable salt thereof:


6. The compound of any of claims 1 to 5, wherein n is
 0. 7. The compoundof any of claims 1 to 6, wherein B¹ is N.
 8. The compound of any ofclaims 1 to 6, wherein B¹ is CH.
 9. The compound of any of claims 1 to8, wherein A¹ is N or CR¹ and R¹ is selected from the group consistingof: H, CN, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl, alkyl-OH, —C₁₋₃ alkyl-OMe,—C(O)NH₂; —C(O)NHMe and —C(O)N(Me)₂.
 10. The compound of any of claims 1to 9, wherein A¹ is CR¹ and R¹ is CN.
 11. The compound of any of claims1 to 10, wherein R² is selected from the group consisting of: H, C₁₋₃alkyl, C₁₋₃ fluoroalkyl, alkyl-OH and —C₁₋₃ alkyl-OMe.
 12. The compoundof any of claims 1 to 11, wherein A² is N or CR³ and R³ is selected fromthe group consisting of: H, C₁₋₃ fluoroalkyl and —C₁₋₃ alkyl-OH.
 13. Thecompound of any of claims 1 to 11, wherein A² is CH.
 14. The compound ofany of claims 1 to 8, wherein the group of the formula:

is selected from the group consisting of:


15. The compound of any of claims 1 to 8, wherein the group of theformula:

is selected from the group consisting of:

For example selected from:


16. The compound of claim 1 selected from:


17. A pharmaceutical formulation comprising a compound of any of claims1 to 16 and a pharmaceutically acceptable excipient.
 18. A compound ofany of claims 1 to 16, for use as a medicament.
 19. A compound of any ofclaims 1 to 16 for use in the treatment of a condition which ismodulated by an AMPA receptor.
 20. A compound of any of claims 1 to 16,for use in the treatment of a depressive disorder or a mood disorder.21. A compound of any of claims 1 to 16, for use in the treatment of atreatment-resistant depressive disorder.
 22. A compound of any of claims1 to 16, for use in the treatment of cognitive dysfunction.
 23. Thecompound for the use of claim 22, wherein the cognitive dysfunction isassociated with a neurological or neuropsychiatric disorder.
 24. Acompound of any of claims 1 to 16 for use in the treatment of a centralnervous system disorder associated with an alteration in one or more ofcognitive function, synaptic plasticity or an imbalance inexcitatory/inhibitory neurotransmission.
 25. A compound for the use ofany of claim 19, 20, 21, 23 or 24, wherein the condition or disorder isselected from: schizophrenia, bipolar disorder, attention-deficithyperactivity disorder, a depressive disorder, a neurodegenerativedisorder (for example Alzheimer's disease, Huntington's disease orParkinson's disease), a neurodevelopmental disorder, a motor neurondisease (for example amyotrophic lateral sclerosis), ataxia, respiratorydepression and a hearing disorder.
 26. A compound of any of claims 1 to16 for use in the treatment of cognitive dysfunction associated withschizophrenia
 27. A compound for the use of any of claims 19 to 26,wherein the compound is co-administered to a subject with an additionaltherapeutic agent.
 28. A compound for the use of claim 27, wherein theadditional therapeutic agent is selected from an antipsychotic and ananti-depressant.
 29. A compound selected from a compound of the formula(XII) or (XIII), or a pharmaceutically acceptable salt thereof:

wherein A², B¹, B², R⁴, X, X¹, a, b, and n are as defined in claim 1.